Роли глюкагонового пептида 1 Агонисты-рецепторы в биологии иммунных клеток и аутоиммунных/аутоинфлампмидативных заболеваниях.

Introduction

Glucagon-like peptide-1 (GLP-1) is derived from the cleavage of proglucagon, a protein produced by the intestinal L cells [ 1 ]. It is primarily known for its role in maintaining glucose balance in the body. GLP-1 achieves this mainly by stimulating insulin secretion and inhibiting the release of glucagon [ 2 ]. GLP-1 performs its biological functions through binding to GLP-1 receptor (GLP-1R), a multifunctional member of the G protein-coupled receptor family, which initiates a downstream signaling cascade [ 3 , 4 ].

GLP-1R was initially discovered on pancreatic β-cells [ 5 , 6 ], highlighting GLP-1’s crucial role in regulating blood sugar homeostasis. The interaction of GLP-1 with the GLP-1R increases insulin secretion in response to glucose and decreases glucagon levels through increasing intracellular cyclic adenosine monophosphate (cAMP) [ 7 ]. Additionally, GLP-1R signaling in β-cells activates mTOR-dependent transcription of hypoxia-inducible factor 1 alpha (HIF-1α), which upregulates glucose expression and promotes glucose metabolism [ 8 , 9 ]. Beyond pancreatic β-cells, GLP-1R is also found on various other cell types, such as neuronal cells, cardiovascular cells, gastrointestinal smooth muscle cells, and immune cells [ 10 – 17 ] (Fig. 1 ). GLP-1 delays gastric emptying via stimulating inhibitory nitrergic myenteric neurons [ 18 ] and activating vagal afferents [ 19 ], leading to reduced gastrointestinal motility [ 20 ]. GLP-1 acts as a satiety hormone [ 21 ], transmitting signals of fullness from the gut to the brain and activating GLP-1R mediated by paracrine activations of vagus afferent neurons innervating the gastrointestinal tract [ 22 , 23 ]. A recent study demonstrated that GLP-1 enhances preingestive satiety through hypothalamic circuits in both mice and humans, with GLP-1R-expressing neurons in the dorsomedial hypothalamus (DMH) emerging as key candidates for encoding this satiety signal [ 24 ]. Moreover, GLP-1 suppresses appetite by inhibiting AMP-activated protein kinase (AMPK) activity in the ventromedial hypothalamus (VMH) [ 25 , 26 ]. Recent research further highlights the critical involvement of the lateral septum (LS) in mediating anorexia-related effects [ 27 ]. A novel study revealed an unexpected functional segregation in hindbrain GLP-1R circuits, identifying two distinct neuronal projections from the area postrema (AP) and nucleus of the solitary tract (NTS) that mediate aversion and satiety, respectively. Importantly, GLP-1RAs maintained their anorexigenic effects even when the aversive pathway was pharmacologically blocked [ 28 ]. Furthermore, comprehensive reviews have provided emerging evidence elucidating the neural mechanisms underlying GLP-1RA action and clarifying the specific role of GLP-1R within distinct brain regions [ 29 – 31 ].

Fig. 1 Immune cells and organs of GLP-1R expression. The distribution of GLP-1Rs in various immune cells as well as in the pancreas, liver, skin, gastrointestinal tract, central nervous system, cardiovascular system, respiratory system, and kidney, and their roles in the corresponding organs are illustrated. Abbreviations: i NKT, invariant natural killer T cell; Treg, regulatory T cell; NK cell, natural killer cell; ILC, innate lymphoid cell; GFR, glomerular filtration rate. Figure created with BioRender.com

Immune cells and organs of GLP-1R expression. The distribution of GLP-1Rs in various immune cells as well as in the pancreas, liver, skin, gastrointestinal tract, central nervous system, cardiovascular system, respiratory system, and kidney, and their roles in the corresponding organs are illustrated. Abbreviations: i NKT, invariant natural killer T cell; Treg, regulatory T cell; NK cell, natural killer cell; ILC, innate lymphoid cell; GFR, glomerular filtration rate. Figure created with BioRender.com

Given its biological effects, activation of GLP-1R has been explored as a latent treatment for metabolic disorders like type 2 diabetes mellitus (T2DM) and obesity. However, natural GLP-1 is quickly broken down by dipeptidyl peptidase 4 (DPP4) after it is released [ 2 ]. To counter this limitation, a group of GLP-1 receptor agonists (GLP-1RAs), which are resistant to DPP4-mediated degradation [ 32 ], have been developed and shown to be effective in treating T2DM and obesity [ 33 ]. Currently, common clinical GLP-1RAs include exenatide and exenatide-LAR [ 34 – 40 ], lixisenatide [ 41 – 44 ], beinaglutide [ 45 ], liraglutide [ 46 – 53 ], semaglutide [ 54 – 58 ], albiglutide [ 59 – 61 ], dulaglutide [ 62 – 64 ], oral semaglutide [ 58 , 65 – 67 ], PEG-loxenatide [ 68 ] and tirzepatide [ 68 – 73 ] (Table 1 ).

Table 1 GLP-1-based drugs GLP-1RAs GLP-1RAs Trade Name Classification Structure Basis Homology to GLP-1 Dosing Frequency Related Application Diseases Reference Exenatide Byetta ® Short acting Exendin-4 53% Twice daily injections Diabetes, Vascular disease, Nonalcoholic steatohepatitis, Nephropathy, Neurodegenerative brain disorder [ 34 – 40 ] Lixisenatide Lyxumia ® Short acting Exendin-4 50% Once daily injection Diabetes, Neurodegenerative brain disorder [ 41 – 44 ] Beinaglutide Besitai Short acting Recombinant native GLP-1 100% Once daily injection Diabetes [ 45 ] Exenatide-LAR Bydureon ® Long acting Exendin-4 53% Weekly injections Diabetes, Vascular disease, Nonalcoholic steatohepatitis, Nephropathy, Neurodegenerative brain disorder [ 34 – 40 ] Liraglutide Victoza ® Saxenda ® Long acting Native GLP-1 97% Once daily injection Diabetes, Vascular disease, Nonalcoholic steatohepatitis, Nephropathy, Neurodegenerative brain disorder, Asthma, Psoriasis, Obesity [ 46 – 53 ] Semaglutide Ozempic ® Wegovy ® Long acting Native GLP-1 94% Weekly injections Diabetes, Nephropathy, Vascular disease, Obesity, Nonalcoholic steatohepatitis [ 54 – 58 ] Albiglutide Eperzan ® Long acting Native GLP-1 97% Weekly injections Diabetes, Vascular disease [ 59 – 61 ] Dulaglutide Trulicity ® Long acting Native GLP-1 90% Weekly injections Diabetes [ 62 – 64 ] Oral semaglutide Rybelsus ® Long acting Native GLP-1 94% Oral once daily Diabetes, Nonalcoholic steatohepatitis [ 58 , 65 – 67 ] PEG-loxenatide Fulaimel Long acting Exendin-4 / Weekly injections Diabetes [ 68 ] Tirzepatide Mounjaro ® Zepbound Long acting GIP/GLP-1 receptor dual agonists / Weekly injections Diabetes, Obesity, Metabolic dysfunction-associated steatohepatitis, Obstructive sleep apnea, Vascular disease [ 68 – 73 ] LAR, long-acting release; GIP, glucose-dependent insulinotropic polypeptide

Table 1 GLP-1-based drugs GLP-1RAs GLP-1RAs Trade Name Classification Structure Basis Homology to GLP-1 Dosing Frequency Related Application Diseases Reference Exenatide Byetta ® Short acting Exendin-4 53% Twice daily injections Diabetes, Vascular disease, Nonalcoholic steatohepatitis, Nephropathy, Neurodegenerative brain disorder [ 34 – 40 ] Lixisenatide Lyxumia ® Short acting Exendin-4 50% Once daily injection Diabetes, Neurodegenerative brain disorder [ 41 – 44 ] Beinaglutide Besitai Short acting Recombinant native GLP-1 100% Once daily injection Diabetes [ 45 ] Exenatide-LAR Bydureon ® Long acting Exendin-4 53% Weekly injections Diabetes, Vascular disease, Nonalcoholic steatohepatitis, Nephropathy, Neurodegenerative brain disorder [ 34 – 40 ] Liraglutide Victoza ® Saxenda ® Long acting Native GLP-1 97% Once daily injection Diabetes, Vascular disease, Nonalcoholic steatohepatitis, Nephropathy, Neurodegenerative brain disorder, Asthma, Psoriasis, Obesity [ 46 – 53 ] Semaglutide Ozempic ® Wegovy ® Long acting Native GLP-1 94% Weekly injections Diabetes, Nephropathy, Vascular disease, Obesity, Nonalcoholic steatohepatitis [ 54 – 58 ] Albiglutide Eperzan ® Long acting Native GLP-1 97% Weekly injections Diabetes, Vascular disease [ 59 – 61 ] Dulaglutide Trulicity ® Long acting Native GLP-1 90% Weekly injections Diabetes [ 62 – 64 ] Oral semaglutide Rybelsus ® Long acting Native GLP-1 94% Oral once daily Diabetes, Nonalcoholic steatohepatitis [ 58 , 65 – 67 ] PEG-loxenatide Fulaimel Long acting Exendin-4 / Weekly injections Diabetes [ 68 ] Tirzepatide Mounjaro ® Zepbound Long acting GIP/GLP-1 receptor dual agonists / Weekly injections Diabetes, Obesity, Metabolic dysfunction-associated steatohepatitis, Obstructive sleep apnea, Vascular disease [ 68 – 73 ] LAR, long-acting release; GIP, glucose-dependent insulinotropic polypeptide

GLP-1-based drugs GLP-1RAs

Victoza ®

Saxenda ®

Ozempic ®

Wegovy ®

Mounjaro ®

Zepbound

LAR, long-acting release; GIP, glucose-dependent insulinotropic polypeptide

Intriguingly, beyond their metabolic benefits, GLP-1RAs also exhibit anti-inflammatory effects. For instance, a meta-analysis has demonstrated a notable reduction in C-reactive protein (CRP) levels following GLP-1RA therapy in individuals with T2DM [ 74 ]. Furthermore, GLP-1RA treatment in patients with T2DM has been linked to decreased secretion of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) by peripheral blood mononuclear cells (PBMC) [ 75 ]. Long-acting GLP-1RAs can also improve the inflammatory response by regulating leptin levels in adipose tissue, which is beneficial for treating obesity-associated diseases [ 76 ]. These observations have prompted further investigation into how GLP-1R signaling regulates immune responses. Indeed, GLP-1R is widely expressed on a variety of immune cells, such as macrophages, lymphocytes and invariant natural killer T cells ( i NKT) [ 77 ], suggesting direct immunological properties of GLP-1R signaling. Considering these immunomodulatory and anti-inflammatory effects, GLP-1RAs are being investigated for their potential in treating inflammation-associated diseases.

This review delves into the present comprehension of GLP-1R signaling in immune cells and emphasizes the therapeutic potential of GLP-1RAs in treating autoimmune and autoinflammatory diseases. We focus on their latent applications in conditions including psoriasis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), asthma, multiple sclerosis (MS), Sjögren’s syndrome (SS), and systemic lupus erythematosus (SLE), highlighting the broader therapeutic benefits of GLP-1RAs beyond their well-established use in managing T2DM and obesity.

Roles of GLP-1R signaling in immune cell biology

Macrophages

Macrophages are multifunctional innate immune cells known for their remarkable phenotypic and functional diversity, playing a significant role in regulating immune reactions and inflammation [ 78 ]. Upon activation, macrophages can be generally classified into two primary types: M1-like and M2-like macrophages [ 79 ]. M1-like macrophages, also known as conventionally activated macrophages, are key players in pro-inflammatory responses. They are distinguished by their capability to produce elevated levels of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α [ 79 ]. These cytokines are essential in the acute phase of inflammation, as they assist in fighting off pathogens. M1-like macrophages are also important in presenting antigens to T cells and promoting Th1 responses, which are critical for defending against intracellular pathogens and tumors [ 80 ]. By contrast, M2-like macrophages, also called alternatively activated macrophages, are mainly associated with anti-inflammatory responses [ 81 ]. They release cytokines like transforming growth factor-beta (TGF-β) and IL-10, which help resolve inflammation and promote tissue repair and remodeling [ 82 ]. M2-like macrophages are essential for wound healing, maintaining tissue balance, and resolving inflammation [ 83 ]. They also help regulate immune responses by affecting other immune cells’ activity [ 84 ]. It is acknowledged that the stimulation of signal transducers and activators of transcription 3 (STAT3) is essential for the transformation into the M2 subtype, whereas the activation of STAT1 is a crucial determinant for the M1 subtype [ 85 ].

GLP-1R is present on both human monocyte-derived macrophages and the murine macrophage cell line RAW264.7 [ 86 , 87 ]. Activation of GLP-1R signaling promotes M2-like macrophage phenotype while inhibiting M1-like macrophages across various models. In detail, GLP-1 treatment leads to a decrease in M1 markers, including IL-6, TNF-α, and inducible NOS ( i NOS), while promoting increased levels of markers of M2 such as IL-10, arginase-1(Arg-1), macrophage galectin-1 (MGL-1), and mannose receptor-1 (MRC-1) in murine RAW264.7 macrophages [ 14 , 79 ].

Mechanistically, activation of GLP-1R by GLP-1 or exenatide phosphorylates STAT3, which drives human monocyte-derived macrophages to develop an M2 phenotype marked by increased expression of CD163, CD204, and IL-10 [ 86 ]. Moreover, GLP-1RA exendin-4 improves insulin resistance by directly inhibiting the activation of nuclear factor-kappa-B (NF-κB) within the murine macrophage cell line RAW264.7 [ 88 , 89 ]. Furthermore, exenatide has been demonstrated to inhibit the pro-inflammatory phenotypes of human PBMC-derived monocytes/macrophages through its regulatory effects on key signaling pathways, including mitogen-activated protein kinase (MAPK), NF-κB and CCAAT/enhancer-binding protein beta (C/EBPβ) [ 90 ]. Exendin-4 also promotes the polarization of bone marrow-derived macrophages in mice towards the M2 subtype by modulating the STAT3 pathway and cAMP protein kinase A (PKA) signaling [ 91 , 92 ]. Beyond the M2-polarization function, GLP-1R activation also supports macrophage migration, which may be mediated by its regulation of macrophage polarization and the effects of IL-6 [ 93 , 94 ]. Interestingly, the activation of macrophages is closely related to their metabolic reprogramming. Semaglutide regulates lipid metabolism and polarization in tumor-associated macrophages (TAMs) through the PPARG/ACSL1 signaling pathway, transforming them from an M2 to an M1 polarized state to inhibit tumor progression. Semaglutide downregulates the transcription factor PPARG, thereby reducing its inhibition of the downstream molecule ACSL1, leading to increased ACSL1 expression and promoting M1 polarization, ultimately enhancing the anti-tumor effects [ 95 ].

Microglia

Glial cells, which include astrocytes and microglia, are essential for maintaining metabolic homeostasis and defending against pathogens within the central nervous system (CNS) [ 96 ]. Following a brain insult, microglia are the first responders, with reactive astrocytes subsequently becoming activated. These glial cells release a variety of pro-inflammatory agents, such as chemokines and cytokines, in order to address the insult [ 97 ]. Tissue-resident macrophages are essential for maintaining tissue homeostasis and preventing excessive immune responses throughout development, health, and disease. Instances of such macrophages encompass Langerhans cells within the skin, alveolar macrophages in the pulmonary tissues, Kupffer cells in the hepatic parenchyma, and osteoclasts in the skeletal structures [ 98 , 99 ]. Microglia, the resident immune cells in the CNS, function as brain macrophages and are essential in modulating neuroinflammation when activated under inflammatory conditions [ 100 , 101 ]. They can adopt various phenotypes, such as the inflammatory-promoting M1 subtype and the inflammation-suppressing M2 phenotype, and secrete different inflammatory mediators in response to inflammation [ 102 – 104 ]. In addition, the latest guidelines classify microglial states into five major phenotypes: homeostatic, DAM-like, HLA/MHC class II, CRM or inflammatory, and interferon (IRM or IFN) clusters [ 105 ].

GLP-1R is expressed on neurons and glial cells across various brain regions [ 106 ]. A previous study has established that the BV-2 cell line derived from microglia can secrete GLP-1 and that GLP-1 secretion is reduced under inflammatory stimulation [ 107 ], suggesting a potential autocrine or paracrine role for GLP-1 signaling within microglia. GLP-1RAs, such as exendin-4 and liraglutide, can reduce neuroinflammation caused by microglia by encouraging a conversion from the pro-inflammatory M1 subtype towards the anti-inflammatory M2 phenotype. This conversion helps to mitigate neuronal apoptosis and damage related to inflammation in mouse models of hypoxic-ischemic encephalopathy and traumatic brain injury (TBI) [ 108 – 110 ].

Mechanistically, GLP-1R activation raises cAMP levels and triggers the PKA/CREB (cAMP-response element-binding protein) signal transduction pathway, which regulates various cellular processes [ 111 ]. Furthermore, liraglutide has been shown to inhibit endoplasmic reticulum stress, as well as related apoptosis and inflammatory reactions are mediated through the cAMP/PKA/CREB pathway in BV2 cells that have been exposed to lipopolysaccharide (LPS) or tunicamycin (TM), a mouse-derived microglial cell line [ 111 ]. Activation of GLP-1R also enhances the levels of anti-inflammatory cytokines like IL-4 and IL-10, along with increasing the expression of the neuroprotective factor β-endorphin in microglia [ 112 ]. Notably, exenatide has been shown to induce the overexpression of β-endorphin and analgesia via an autocrine secretion of IL-10, instead of IL-4. This occurs via the signaling pathways of IL-10/IL-10 receptor-α/STAT3 and cAMP/PKA/p38β/CREB [ 112 ]. Moreover, exendin-4 inhibits NF-κB activity by hindering the breakdown of IκBα (NF-kappa-B inhibitor alpha) in LPS-stimulated primary microglia, which reduces the activation of microglia and the generation of pro-inflammatory cytokines [ 113 ]. Altogether, the GLP-1R signaling pathway is essential for reducing neuroinflammation by regulating microglia function and polarization [ 114 ].

Monocytes

Monocytes, which originate in the bone marrow, are among the first responders to infection and injury in both the vasculature and tissues [ 115 ]. During inflammation, blood monocytes move from the bloodstream to both lymphatic and non-lymphatic tissues. In these tissues, they perform several functions: phagocytosing and degrading foreign cells and harmful substances like oxidized LDL (ox-LDL), secreting pro-inflammatory cytokines, and differentiating into diverse immune cell types, such as inflammatory dendritic cells (DCs), macrophages, or foam cells [ 116 – 118 ].

Reportedly, GLP-1R is expressed on monocytes [ 119 ]. Exendin-4 activation of GLP-1R in human monocytes reduced pro-inflammatory cytokine production and foam cell formation [ 15 ]. In addition, exendin-4 treatment reduced lipid accumulation in human primary monocytes and THP-1-derived macrophages stimulated by ox-LDL [ 15 ]. Notably, the GLP-1RA liraglutide stimulates the secretion of IL-6 in monocytes, which in turn promotes brown adipocyte differentiation and heat production. This mechanism is responsible for its anti-diabetic properties. These findings highlight the direct impact of the temporary activation of the GLP-1-IL-6 axis in adipocytes, which contributes to regulating the overall balance of the metabolism of glucose and lipids in the body [ 120 ]. Nevertheless, the exact mechanism by which GLP-1 analogues promote IL-6 expression in monocytes is still unclear. Significantly, it has been demonstrated that GLP-1 analogues can suppress NF-κB, which is a major activator of IL-6 expression [ 121 ]. It is speculated that this signaling may be mediated by CREB, which is known to act downstream of GLP-1R and may influence the transcription of IL-6 [ 122 – 124 ].

Granulocytes

Hematopoietic stem cells (HSCs) derived from bone marrow develop into immature myeloid cells, which then differentiate into monocytes (further develop into macrophages and DCs) and granulocytes (including neutrophils, basophils, and eosinophils) [ 125 ]. The dysfunction of hematopoietic stem and progenitor cells drives inflammation-related myelopoiesis, which maintains neutrophil populations and promotes chronic inflammation [ 126 ]. The inflammatory response often involves the infiltration of immune cells [ 127 ].

GLP-1R is expressed on neutrophils and eosinophils [ 128 , 129 ], and its expression on basophils has not yet been reported. In the context of an acute inflammatory state, neutrophils are the initial immune cells that move into tissues, where they secrete chemokines to expedite the recruitment of monocytes into these tissues [ 130 ]. Neutrophils quickly migrate to the infection site through a multi-step process involving tethering, rolling, adhesion, and transmigration into tissue [ 131 ]. CD11b serves as the alpha chain within the integrin CD11b/CD18 complex, which is found on the membranes of invading macrophages and neutrophils. It is involved in several biological processes, such as cell adhesion, migration, and signaling [ 132 ]. A recent study demonstrated that semaglutide, a long-acting GLP-1RA, inhibits the expression of CD11b on neutrophils and further affects their migration and endothelial adhesion functions [ 128 ]. Eosinophils are known to contribute significantly to Th2 immunity by modulating local immune and inflammatory responses [ 133 ]. It has been demonstrated that basophils can regulate the entry of eosinophils into sites of inflammatory tissue through activation-induced interactions with endothelial cells [ 134 ]. The GLP-1RA liraglutide significantly reduces the eosinophilia and the production of type-2 cytokines species like IL-5 and IL-13 in the respiratory tract, while GLP-1R signaling downregulates innate allergic inflammation [ 135 ]. Additionally, it has been reported that GLP-1 analogues may inhibit markers of eosinophil activation and the production of Th2 cytokines. The functional effects of GLP-1 analogues on human eosinophils appear to be linked to their ability to reduce LPS-induced membrane expression of CD69 and CD11b, along with the synthesis of cytokines like IL-4, IL-8, and IL-13 [ 129 ].

T cells

T lymphocytes, or T cells, are derived from progenitors in the bone marrow, which then travel to the thymus for maturation and selection before being released into the peripheral circulation [ 136 ]. T cells are classified into two primary groups: αβ T cells and γδ T cells, distinguished by the structure of their cell receptors [ 137 ]. Furthermore, αβ T cells are divided into CD4 and CD8 subsets, while γδ T cells and NKT cells represent distinct subpopulations [ 138 ]. i NKT cells are a specific subset of NKT cells [ 139 ]. They are considered a population of innate T lymphocytes, meaning they possess characteristics of both innate and adaptive immune cells. This unique feature allows them to act as a bridge between the two types of immune responses. Depending on the environment, i NKT cells can either initiate or suppress the immune response and make up the majority of NKT cells [ 140 ].

CD4 + T cells

CD4⁺ T cells assume a pivotal function in the immune system as they achieve this by orchestrating the immune response through cytokine secretion. These cells are predominantly classified into two categories: regulatory T cells (Tregs) and effector T cells. The effector T cells can be additionally partitioned into distinct subsets according to their cytokine profiles and genetic expression patterns. These subsets encompass T helper (Th) cells, which are composed of Th1, Th2, Th9, Th17, Th22 cells, as well as T follicular helper (TFH) cells [ 141 ]. The balance between Th17 cells and Tregs is essential for maintaining immune homeostasis and influencing disease outcomes [ 142 ]. Tregs secrete immunosuppressive factors like IL-10 and transforming growth factor beta 1 (TGF-β1), contributing to decreasing inflammation, supporting tissue repair, and preserving immune tolerance [ 143 ]. In contrast, Th17 cells are distinguished by the secretion of pro-inflammatory cytokines, such as IL-17 and IL-21, which are of great significance in initiating inflammatory responses and combating specific pathogens [ 144 ].

Activated T cells have been shown to express GLP-1R, and this expression is functional. Treatment with a GLP-1RA results in a rise in intracellular cAMP, and this increase can be suppressed by GLP-1R antagonists [ 12 , 13 ]. An examination of the differentiation of CD4⁺ T cells under diverse conditions, such as those promoting the development of Th1, Th2, Th17 cells, and Tregs, demonstrated that the GLP-1R was most prominently expressed on induced regulatory T cells ( i Tregs) [ 13 ]. In addition, activation of T cells in the context of Th1-polarizing and Th17-polarizing requirements with the GLP-1RA liraglutide led to reduced differentiation of Th1 and Th17 cells, while there was no observable change in the number of Tregs [ 145 ]. However, it has been suggested that GLP-1RAs may enhance their anti-inflammatory effects by increasing the number of peripheral Tregs [ 12 , 146 ]. From a mechanistic perspective, GLP-1RAs like exenatide notably decreased the percentage of Th17 cells while promoting the proliferation of Tregs by influencing the signaling cascade encompassing phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), along with forkhead box O1 (FoxO1) [ 147 ]. Beyond its effects on T cell differentiation, GLP-1 also inhibits the migration of CD4 + T cells induced by chemokines by reducing the phosphorylation of PI3K, which is a key signaling pathway in the migration process [ 148 ].

In vivo experiments have shown that mice on a high-fat diet (HFD) treated with liraglutide displayed reduced concentrations of pro-inflammatory cytokines, such as interferon-gamma (IFN-γ) and IL-17, IL-22. This decrease was correlated with a rise in Tregs and a decline in Th17 cells within the splenic tissue [ 149 ]. Additionally, liraglutide also appears to enhance the suppressive effects of Tregs, as evidenced by reduced CD8 + T cell proliferation in co-culture assays involving Tregs in mice treated with GLP-1 analogues [ 149 ].

γδ T cells

γδ T cells constitute an unconventional subpopulation of T cells. They account for a comparatively small fraction of lymphocytes in healthy circulation while being substantially more numerous in mucosal and epithelial tissues [ 150 ]. Distinguished from αβ T cells, γδ T cells have distinct characteristics that greatly affect their roles in disease development and immunotherapy [ 151 ]. As opposed to αβ T cells, γδ T cells are not limited by major histocompatibility complex (MHC) molecules [ 152 ]. This feature enables γδ T cells to be quickly activated in response to molecular signals from infections or tumors, causing the synthesis of considerable volumes of inflammatory-promoting cytokines and chemokines [ 153 , 154 ]. Recent research has identified the expression of GLP-1R on unconventional T cells, such as hepatic γδ T cells [ 155 ]. The function of γδ T cells regarding the secretion of IFN-γ or IL-17 A may vary based on their specific lineage [ 156 ]. Moreover, clinical investigations have revealed that GLP-1 analogues can alleviate the severity of psoriasis in patients with T2DM. This amelioration is correlated with a decline in dermal γδ T cells as well as a diminishment in IL-17 expression [ 157 ]. Despite these findings, the direct impact of GLP-1R signaling on γδ T cell biology remains to be fully elucidated.

iNKT cells

i NKT cells are a specialized subset of unconventional T cells, exhibiting features shared by both natural killer (NK) cells and T cells [ 158 ]. They are distinguished by their consistent T cell receptor (TCR) that detects lipid-based antigens presented by CD1d glycoproteins. These molecules share structural similarities with major histocompatibility complex class I (MHC-I) proteins [ 159 ]. i NKT cells can produce various cytokines, both pro-inflammatory and anti-inflammatory, meaning their involvement in immune responses can be either protective or harmful depending on the environment [ 160 ]. Research has shown that GLP-1R are present on i NKT cells. Stimulation of these cells with either native GLP-1 or the GLP-1 analogue liraglutide results in a substantial decrease in the synthesis of IL-4 and IFN-γ in vitro [ 77 ]. Importantly, liraglutide has been found to modulate cytokine production in i NKT cells without impairing their cytotoxic function [ 77 ].

A distinct regulatory subpopulation of i NKT cells, termed adipose i NKT cells, has been found to be diminished in individuals with obesity. However, the activation of i NKT cells with their prototypical lipid ligand, α-galactosylceramide (αGalCer), has been observed to result in their amplification, which in turn has been demonstrated to induce effective weight loss [ 161 , 162 ]. Research findings have shown that the stimulation of i NKT cells by liraglutide is correlated with the triggering of fibroblast growth factor 21 (FGF21) synthesis, which subsequently results in weight loss [ 163 ]. Liraglutide’s induction of FGF21 requires a functional i NKT cell system because liraglutide promotes satiety but fails to induce FGF21 in i NKT-deficient mice, resulting in a lesser loss of weight [ 163 ]. Furthermore, this study highlights the potential impact of the i NKT cell-FGF21 axis as a novel immune-mediated pathway for glycemic control and body weight regulation [ 163 ].

Other T cells

Intestinal intraepithelial lymphocytes (IELs) serve as the primary defense of the intestinal barrier and are mainly composed of CD8 + T cells [ 164 ]. IELs can be classified into two principal subpopulations: “natural” IELs and “induced” IELs. Natural IELs attain their activated phenotype during their maturation in the thymus, where they are exposed to self-antigens. In contrast, induced IELs originate from typical T cells that undergo further differentiation processes in the intestine in response to exogenous antigens [ 164 ]. Latest research indicated that the gut IELs expressing GLP-1R are pivotal in mediating the impacts of GLP-1RAs. This process involves regulating GLP-1R-dependent signaling within specific subsets of gut microbiota and controlling T cell-driven inflammation [ 165 ]. These findings showed a decrease in the production and secretion of IFN-γ by IELs in the gut following the administration of the GLP-1RAs semaglutide and exendin-4 [ 165 ].

Intriguingly, a recent study has confirmed that GLP-1R acts as a negative co-stimulatory molecule on T cells. The signaling pathway of GLP-1R is of great significance in modulating the immune reaction of these T cells, which is closely linked to their activation, apoptosis, metabolism, and migratory capacity [ 16 ]. This research discovered that the expression level of GLP-1R rose during the alloimmune reaction, paralleling the expression profile of programmed death 1 (PD-1). By modulating GLP-1R signaling, it is possible to influence the survival of alloimmune grafts and the growth of tumors, providing new strategies for immune regulation and cancer therapy [ 16 ].

T lymphocytes in individuals suffering from chronic obstructive pulmonary disease (COPD) have been found to be immunodeficient, with an increased functional exhaustion of T cells that express PD-1, a negative co-stimulatory molecule linked to impaired immune responses [ 166 ]. In addition, patients with more severe stages of COPD had a lower percentage of IFN-γ + CD8 + T cells when contrasted to those at milder disease stages [ 167 ]. There is one study demonstrated a positive correlation between IFN-γ production and GLP-1R expression in patients with COPD. Furthermore, GLP-1R expression was found to be reduced in circulating PBMCs of these patients [ 168 ]. The death of lymphocyte populations expressing PD-1 and the increased production of IFN-γ following liraglutide treatment suggest that restoring GLP-1R signaling may have a regulatory effect on both innate and adaptive immunity. This restoration could potentially improve the functional defects of T cells in patients with COPD [ 168 ].

Innate lymphoid cells

Innate lymphoid cells (ILCs) are indispensable elements of the innate immune system. They play crucial roles in defending against pathogens, maintaining tissue homeostasis, and regulating tissue remodeling [ 169 ]. ILCs are a various group consisting of NK cells, group 1 innate lymphocytes (ILC1s), group 2 innate lymphocytes (ILC2s), group 3 innate lymphocytes (ILC3s), and regulatory innate lymphocytes (ILCregs). Each type of ILCs is characterized by its specific cytokine secretion profile and transcription factor expression, which correspond to the classical T cell subsets [ 170 ].

NK cells assume a significant function in the innate immune system, renowned for their capacity to identify and eliminate a diverse range of distressed cells, including tumor cells and virus-infected cells [ 171 ]. Cellular cytotoxicity, which is the ability to kill other cells, serves as an essential mechanism of the immune system against viral infections and cancer [ 172 ]. NK cells mediate cytotoxicity via two distinct mechanisms. One involves the secretion of cytotoxic granules containing perforin and granzyme, while the other triggers apoptosis through death receptor pathways by expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Fas ligand (FasL). These ligands bind to TRAIL receptors 1 and 2 (TRAIL-R1/-R2) or the CD95/Fas receptor on target cells, ultimately inducing cell death [ 172 ]. Recent studies have demonstrated that GLP-1 therapy improves NK cell cytotoxicity. This is supported by cell-killing assays which indicate increased lysis of NK cell-sensitive lines after GLP-1 treatment, alongside heightened production of IFN-γ and granzyme B [ 173 ]. Within the tumor microenvironment, the IL-6/STAT3 pathway enhances tumor cell survival, proliferation, and invasiveness while simultaneously dampening antitumor immune responses. Consequently, IL-6/STAT3 signaling is correlated with tumor progression, invasion, and immune evasion [ 174 ]. Moreover, IL-6/STAT3 activation can impair innate antitumor immunity by suppressing the activity of NK cells [ 175 ]. Recent research has demonstrated that liraglutide boosts the antitumor function of NK cells by inhibiting IL-6/STAT3 signal transduction. The study highlighted that liraglutide’s antitumor effects are predominantly driven by NK cells instead of CD8 + T cells, suggesting its potential as a novel cancer therapy through innate immune modulation [ 176 ].

ILC2s exhibit the expression of GATA-binding protein 3 (GATA3) and are directly activated by cytokines originating from epithelial cells, like IL-25 and IL-33 [ 177 ]. Research on both mice and humans has highlighted the essential role of IL-33 in stimulating ILC2s and Th2 cells to secrete type 2 cytokines, such as IL-5 and IL-13, which trigger allergic responses driven by the innate immune system [ 178 – 180 ]. It has been reported that GLP-1RA liraglutide significantly reduces innate allergic inflammation caused by airborne allergens. This effect is associated with the release and activation of ILC2s in the lungs of mice [ 135 ]. Notably, liraglutide was found to substantially decrease the production of IL-5 and IL-13 by ILC2s in the pulmonary tissues. This reduction is induced by a decline in the secretion of IL-33 in murine models [ 135 ].

ILC3s constitute a unique subgroup of ILCs defined by their presentation of the retinoid orphan receptor gamma t (RORγt) and their capacity to secrete type 17 cytokines, including IL-17 and IL-22 [ 181 , 182 ]. ILC3s have been recognized to exert a protective function in both adoptive T-cell transfer-induced colitis and dextran sulfate sodium (DSS)-provoked colitis through their production of IL-22. Conversely, blocking IL-22 production has been shown to worsen the condition of colitis [ 183 , 184 ]. A recent study reported that GLP-1RA liraglutide ameliorated DSS-induced colitis by modulating ILC3s and that GLP-1RA promoted IL-22 production by ILC3s, which ameliorated histological damage [ 185 ].

Previous research has demonstrated that GLP-1R knockout (KO) mice exhibit higher basal blood glucose concentrations compared to wild-type (WT) mice [ 186 ], along with impaired cerebral responses to exogenous glucose [ 187 ]. Additionally, studies indicate that the absence of GLP-1R signaling in GLP-1R −/− mice impairs proliferative responses, resulting in increased infiltration of immune cells, including neutrophils and T cells [ 12 , 145 ]. A recent study involving genetic regulation and pharmacological experiments in GLP-1R KO mice confirmed that GLP-1R signaling may be immunoregulatory, and that GLP-1R deficiency accelerates rejection reactions in a chronic heart transplant model induced by CTLA4-Ig (cytotoxic T lymphocyte-associated antigen-4) tolerance [ 16 ]. Furthermore, a comprehensive study utilizing Glp-1R Tcell+/+ and Glp-1R Tcell−/− mice demonstrated that, in the setting of T cell–mediated inflammation within IELs, the anti-inflammatory and tissue-protective effects of GLP-1RAs, both systemically and in the gut, were abolished in the absence of GLP-1R expression in T cells [ 165 ]. Emerging research employed lentivirus-mediated shRNA to knock down GLP-1R expression in vitro, resulting in diminished effects of GLP-1RAs on mitochondrial function by day 21, along with impaired mitochondrial autophagy and autophagic clearance. These results suggest that GLP-1R activation plays a critical role in promoting autophagy in CAR T cells [ 188 ].

Findings from a 4-day Alternaria alternata extract intranasal challenge model showed that the absence of GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling exacerbated airway inflammation, characterized by increased lung ILC2s, lymphocytes, eosinophils, and neutrophils, as well as heightened pulmonary expression of type 2 cytokines (IL-5, IL-13), chemokines (CCL11, CCL24), and epithelial ICAM-1. Conversely, no significant differences in type 2 inflammatory markers were observed between treatment with a GLP-1R/GIPR dual agonist and single GLP-1R or GIPR agonists [ 189 ]. Given these findings, future clinical trials should further evaluate the therapeutic potential of GLP-1R and dual GLP-1/GIPR agonists in mitigating airway inflammation in asthma and other inflammatory diseases.

In brief, GLP-1R is found on various immune cells, and the GLP-1R signaling pathway contributes to the regulation of immune cell function. Nevertheless, there remains a paucity of research regarding the function of the GLP-1R signaling pathway in the modulation of other immune cell types, including DCs, B cells, and mast cells. Consequently, more comprehensive and in-depth investigations are necessary to ascertain whether immune cells truly express GLP-1R and to comprehend how GLP-1R signaling could directly influence the biology of immune cells.

Roles of GLP-1RAs signaling in autoimmune and autoinflammatory diseases

Psoriasis

Psoriasis is a persistent, non-contagious, incurable inflammatory condition that is distinguished by erythematous plaques covered with silvery-white scales on the skin [ 190 , 191 ]. The development of psoriasis is primarily associated with the TNF-α/IL-23/IL-17 A axis [ 192 – 194 ]. Various immune cells contribute to the progression of psoriasis, such as DCs, macrophages, as well as Th17 cells [ 195 ]. Psoriatic skin is characterized by excessive proliferation and abnormal differentiation of keratinocytes. This condition also leads to redness, which is caused by increased blood vessel dilation in the dermis and the infiltration of immune cells, particularly T cells [ 196 ]. GLP-1Rs are found on various cell types involved in psoriasis, such as macrophages, monocytes, T cells, and keratinocytes [ 5 , 197 , 198 ]. Psoriasis has increasingly been linked to metabolic disorders such as diabetes, obesity, and dyslipidemia [ 199 , 200 ]. Emerging evidence suggests that GLP-1RAs may offer potential benefits for psoriasis patients by modulating common immune and inflammatory signaling pathways [ 201 , 202 ]. However, based on current research data, metabolic factors cannot be ruled out as potential contributing factors. Therefore, while GLP-1RAs may represent a promising therapeutic option for managing psoriasis, further high-quality studies are needed to distinguish whether the therapeutic effects of GLP-1RAs originate from the direct regulation of immune cells or improvements in comorbidities such as obesity or diabetes.

A growing number of evidence indicates that GLP-1-based therapies have anti-inflammatory effects in various cells, tissues, and organs by reducing the synthesis of pro-inflammatory cytokines and limiting immune cell infiltration. GLP-1RAs might have a direct impact on keratinocytes, as evidenced by the detection of GLP-1R and glucagon in neonatal mouse skin and cultured skin cells [ 203 ]. In vitro experiments have shown that liraglutide significantly reduces the proliferation of keratinocytes, inhibits the migration of macrophages to keratinocytes, and impairs the inflammatory reactions triggered by LPS in keratinocytes. Moreover, it significantly decreases the synthesis of TNF-α and IL-6 by activating the AMPK phosphorylation pathway [ 197 ]. In addition, the application of exendin-4, a GLP-1RA in obese mice triggered by diet restores C1q/TNF-related protein 3 (CTRP3) expression in keratinocytes, thereby inhibiting STAT3 phosphorylation via lysosomal-associated membrane protein 1 (LAMP1) and alleviating the psoriatic symptoms induced by imiquimod treatment [ 204 ]. In a psoriasis-like skin model induced with imiquimod in obese diabetic mice, treatment with liraglutide has been demonstrated to decrease psoriasis clinical scores and downregulate major inflammatory cytokines, which include IL-17, IL-22, IL-23 and TNF-α [ 205 ]. These findings suggest that GLP-1RAs may offer therapeutic benefits for psoriasis patients, particularly those with coexisting metabolic disorders.

Dermal γδT cells, recognized for their high-level production of IL-17, are of great significance in the progression of psoriasis [ 206 , 207 ]. A prospective case series study found that GLP-1RAs, such as liraglutide and exenatide, reduced the population of cutaneous γδT cells and the expression of IL-17 in skin lesions. This resulted in improved clinical and histopathological outcomes for psoriasis patients with T2DM [ 157 ]. Furthermore, GLP-1RAs have been shown to mitigate psoriasis severity by modulating the innate immune system, specifically through interactions with i NKT cells [ 208 ]. In a study of two psoriasis patients with diabetes, liraglutide therapy for 6 weeks resulted in rapid clinical improvement, characterized by increased circulating i NKT cells and they also demonstrated in vitro that GLP-1 induced a dose-dependent reduction of cytokine secretion from i NKT cells [ 77 ]. A randomized controlled trial (RCT) involving 25 patients with psoriasis and T2DM demonstrated that 12 weeks of treatment with liraglutide caused a marked decline in the Psoriasis Area and Severity Index (PASI) score. Additionally, the treatment was associated with decreased expression magnitudes of pro-inflammatory cytokines, including IL-17, IL-23, and TNF-α, in the affected skin tissue [ 201 ]. However, a randomized placebo-controlled trial evaluating liraglutide in glucose-tolerant obese psoriasis patients showed no significant changes in PASI or Dermatology Life Quality Index (DLQI) scores after 8 weeks of treatment compared with placebo treatment [ 209 ]. A recently updated meta-analysis of four prospective cohort studies and two RCTs involving a total of 63 patients with psoriasis has shown that treatment with GLP-1RAs leads to significant reductions in disease severity, regardless of whether the patients have diabetes [ 210 ]. There is also a case report of the GLP-1RA liraglutide, in combination with acitretin in a 54-year-old obese non-diabetic man who was effectively treated for extensive plaque psoriasis [ 211 ]. Therefore, randomized placebo-controlled trials in patients with psoriasis comorbid with and without T2DM are also needed to take into account the impact of comorbid diabetes or obesity, the placebo effect as well as the natural course of psoriasis. At the same time, in various inflammatory models in animal experiments, we can compare the differences in the anti-inflammatory effects of GLP-1RAs between normal mice and obese or diabetic mice in the future.

Inflammatory bowel disease

IBD, encompassing primary types like ulcerative colitis (UC) and Crohn’s disease (CD), is defined by persistent gut inflammation resulting from a breakdown in immune tolerance to antigens normally present in the intestinal lumen [ 212 ]. Although the exact etiology remains unclear, both UC and CD are thought to result from uncontrolled inflammation and immune dysregulation in genetically predisposed individuals [ 213 ]. Intestinal innate immunity is generated by neutrophils, monocytes, macrophages, and DCs, as well as ILCs and NK cells, characterized by their capacity to produce a rapid and non-specific reaction as a first-line response [ 214 ]. Evidence indicates that dysfunctions in both inherent and adaptive immune pathways significantly contribute to the aberrant intestinal inflammation observed in IBD patients [ 215 ]. It is widely accepted that CD is predominantly propelled by a Th1-mediated response, whereas UC is linked to an atypical Th2 response [ 216 ]. Beyond the classical Th1 and Th2 pathways, the role of Th17 cells has also been identified. Th17 cells, a subset of pro-inflammatory T cells, proliferate in response to the inflammatory cytokine IL-23 [ 217 ].

Mechanistically, an in vitro study found that exendin-4 inhibited the secretion of IL-1α and TNF-α from mouse colonic smooth muscle cells (CSMCs) via the pathway mediated by cAMP and NF-κB, thereby exerting anti-inflammatory effects [ 218 ]. In addition, a study using LPS-exposed RAW264.7 macrophages and a DSS-triggered colitis murine model demonstrated that GLP-1 attenuates inflammatory responses by inhibiting the phosphorylation process of AKT/NF-κB and MAPK signal-transducing molecules under in vitro and in vivo circumstances, respectively [ 219 ]. GLP-1 may impact IBD through several mechanisms, including the modulation of T-cell maturation and activity, adjustment of innate immune cell populations, like macrophages and DCs, suppression of inflammatory cytokines generation, and enhancement of tissue repair in damaged epithelium [ 220 ].

Ample evidence indicates that therapies aimed at pro-inflammatory cytokines like IL-6, IL-1β and TNF-α are of great significance in the pathogenesis of IBD and contribute to the prevention of tissue damage [ 221 , 222 ]. Numerous animal research has demonstrated the possible anti-inflammatory effects of GLP-1RAs in treating IBD. For instance, the administration of GLP-1 nanomedicine resulted in a decrease in IL-1β, a pro-inflammatory cytokine, and a marked improvement of the architecture of the intestinal epithelium in a colitis model [ 223 ]. Furthermore, a study found that intraperitoneal injection of GLP-1 (Beinaglutide Injection) alleviates tissue injury effects in DSS-induced colitis mice by inhibiting intestinal inflammation, preserving the intestinal barrier, and modulating intestinal microbiota [ 219 ]. A study conducted on a mouse model of colitis found that the GLP-1RA liraglutide significantly improves IBD activity. This improvement is reflected in a reduction in the histopathological score of colonic tissues and a decreased colon weight-to-length ratio. The mechanism involves the suppression of pro-inflammatory chemokine (C-C motif) ligand 20 (CCL20), which is of significant importance in the Th17 immune response, as well as IL-33, which is a key cytokine associated with Th2 immune responses [ 224 ]. Moreover, a recent investigation employed a murine model of colitis that was triggered by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and found that disturbances in glucose levels were correlated with GLP-1 levels. This suggests that changes in the incretin system during colitis may influence blood glucose levels and may act as a prospective novel therapeutic target for CD [ 225 ].

These investigations demonstrate that GLP-1RAs have the potential to influence important pathways linked to the development of IBD. These pathways include chronic inflammation, the integrity of intestinal epithelial tight junctions, and disruptions in the gut microbiota. This provides a foundation for conducting clinical trials in humans to explore the efficacy of GLP-1RAs in treating IBD patients, particularly in populations with metabolic disorders [ 226 ]. A large epidemiological study involving 3,751 patients with both IBD and T2DM compared various antidiabetic treatments. Among these patients, 982 were treated by applying GLP-1RAs or DPP-4 inhibitors, while 2,769 received other antidiabetic medications. The findings indicated that patients on GLP-1RAs and/or DPP-4 inhibitors experienced better disease outcomes compared to those on different treatments, accompanied by an incidence rate ratio (IRR) of 0.52 (95% confidence interval: 0.42–0.65) [ 227 ]. Additionally, a case report highlighted that liraglutide therapy, in contrast to insulin, reduced C-peptide (CPR) concentrations and improved glucose control, along with enhanced quality of life for a patient with T2DM and active CD [ 228 ]. Evidence supports the potential benefits of GLP-1RAs in IBD management, yet current data do not rule out metabolic factors as contributing to these benefits. In the future, a multidimensional line of evidence is needed to clarify the source of GLP-1RA effects in IBD, including in vitro experiments to confirm direct actions, animal models designed to exclude metabolic interference, and clinical data adjusted for metabolic confounders.

Rheumatoid arthritis

RA is a long-standing autoimmune inflammatory disorder with an undetermined pathogenesis. It is distinguished by synovitis, continuous joint inflammation, and a diverse range of systemic comorbidities [ 229 , 230 ]. Research has demonstrated that multiple immune cells are involved in the etiology and evolution of RA, including macrophages, monocytes, neutrophils, and T cells [ 231 ]. As mentioned earlier, given that GLP-1RAs have a regulatory impact on these immune cells, they could potentially serve as a therapeutic target for RA. However, there is still a lack of reports on the regulatory effect of GLP-1RAs on immune cells in RA. Notably, another important cell involved in the pathogenic process of RA is the fibroblast-like synoviocytes (FLSs), and there are more available studies that examine the effects of GLP-1RAs on FLSs. Crucial cytokines including IL-1β, IL-6 and TNF-α are essential for sustaining the chronic inflammatory state associated with RA [ 232 , 233 ]. TNF-α is found at high levels in the synovium of patients with RA [ 234 ], while IL-1β is recognized as a major contributor to inflammation in the disease [ 235 ]. Additionally, IL-6 can be secreted by FLSs and B cells in the RA synovium and has been closely linked to the pathogenesis of the disease [ 236 ].

FLSs are crucial effector cells in the development of RA. Their abnormal proliferation causes synovial thickening, increased inflammation, and joint damage [ 237 , 238 ]. A study has shown that lixisenatide inhibits inflammation of RA in human FLSs by downregulating IL-6, IL-8 and TNF-α, while also inhibiting cellular communication pathways including c-Jun N-terminal kinase (JNK) and NF-κB [ 239 ]. Similarly, exenatide ameliorated the inflammatory response in human RA FLSs by decreasing the oxidative stress capacity of FLSs and down-regulating the expression of IL-1β and IL-6, while suppressing the initiation of p38/MAPK and NF-κB signal transduction pathways [ 240 ]. Furthermore, dulaglutide, another GLP-1RA, was found to improve mitochondrial dysfunction and oxidative stress caused by TNF-α in human FLSs. This effect occurs through the JNK/NF-κB signaling pathway [ 241 ]. Additionally, dulaglutide reduced the production of pro-inflammatory molecules monocyte chemoattractant protein-1 (MCP-1), IL-6 and IL-1β in FLSs, underscoring its strong anti-inflammatory properties [ 241 ].

Asthma

Asthma is classified as a widespread chronic inflammatory malady, affecting an estimated 4% of the global population [ 242 ]. It is classically characterized as an “allergic” disease associated with type 2 inflammation [ 243 ]. In addition, eosinophils are associated with eosinophilic asthma, which usually manifests as a type 2 inflammatory response [ 244 ]. The type 2 inflammatory response is primarily driven by cytokines like IL-4, IL-5, and IL-13, together with other inflammatory agents produced by Th2 cells and ILC2s [ 245 , 246 ]. Interestingly, GLP-1Rs are abundantly expressed not only in the pancreas and gastrointestinal tract but also in other organs, such as the lung [ 247 ].

In an asthma mouse model, the administration of liraglutide led to a reduction in the expression of IL-33 and a decline in the infiltration of eosinophils and ILC2s in lung tissue. It also lowered the secretion of cytokines IL-5 and IL-13 that belong to type 2 inflammation by ILC2s, suggesting that GLP-1R signaling may inhibit innate allergic immune responses in the lung [ 135 ]. Another study indicated that GLP-1RAs such as exenatide and liraglutide effectively improve ovalbumin (OVA)-induced asthma by reducing airway mucus hypersecretion and inflammatory responses in mice through PKA-dependent NF-κB inactivation [ 248 ]. Liraglutide has been found to reduce eosinophilic airway inflammation, airway hyperreactivity (AHR), and the amounts of IL-4, IL-5, and IL-33 within an obesity mouse model of asthma induced by HFD. This study suggests that GLP-1RAs could be promising new therapeutic agents for obese asthma patients, particularly due to their impact on the expression of IL-1β modulated by nucleotide oligomerization domain-like receptor protein 3 (NLRP3) [ 249 ].

Obesity is linked to a higher risk of developing asthma and an increase in asthma severity [ 250 , 251 ]. A study conducted on a mouse model of obesity combined with asthma demonstrated that the GLP-1RA liraglutide effectively reduces airway inflammation. It achieves this by inhibiting neutrophilia triggered by aeroallergens and decreasing the release of IL-5 and IL-13. These findings suggest that GLP-1RAs could represent a promising pharmacological approach for treating asthma in obese patients [ 47 ]. Furthermore, in a model of pulmonary fibrosis induced by bleomycin, liraglutide treatment inhibited immune cell infiltration and reduced TGF-β1 levels. It also significantly attenuated bleomycin-triggered initiation of NF-κB and vascular cell adhesion molecule-1 (VCAM-1) [ 252 ].

Asthma is often comorbid with T2DM and obesity [ 253 , 254 ]. A recent retrospective cohort study found that patients with T2DM on GLP-1RAs experienced fewer asthma exacerbations compared to those on other anti-glycemic agents, having a comparative incidence rate ratio that covers the range of 1.83 to 2.98 [ 255 ]. Additionally, a pooled analysis of large-scale clinical studies evaluating the cardiorenal advantages of GLP-1RAs in T2DM suggested a trend towards reduced pulmonary adverse events, including asthma, in the GLP-1RAs treatment groups [ 256 ]. Meanwhile, a recently published meta-analysis comprehensively examined the relationship between the probability of asthma incidents and the application of GLP-1RAs for patients diagnosed with T2DM and obesity. In their study, fewer asthma events were observed in GLP-1RAs users than in non-users, but the difference was not significant at the statistical level [ 257 ].

In conclusion, GLP-1RAs show promising therapeutic efficacy in patients with both asthma and metabolic disorders. However, due to the limited research on the use of GLP-1RAs specifically for asthma treatment, future studies are needed to determine whether these drugs should be included in the anti-asthma treatment repertoire and to investigate whether their effects are mediated through direct regulation of immune cells.

Multiple sclerosis

MS is a persistent, demyelinating, neurodegenerative, inflammatory illness of the CNS [ 258 ]. It is typified by the penetration of immune cells through the blood-brain barrier (BBB) and the formation of lesions, which are key indicators of the disease. These lesions are associated with inflammation, demyelination, glial activation, and neuroaxonal degeneration, leading to compromised neuronal signaling [ 106 ]. The development of MS is closely related to innate immune cells, namely macrophages, microglia, and NK cells, as well as adaptive immune cells like T lymphocytes [ 259 ].

Experimental autoimmune encephalitis (EAE) is a well-established animal model that accurately mimics the CNS demyelinating lesions and T-cell responses observed in MS [ 260 ]. It is extensively utilized to investigate the pathophysiology of MS and to assess potential new treatments [ 261 ]. Recent research has highlighted the neuroprotective effects of GLP-1RAs in this model. For instance, semaglutide, a novel GLP-1RA, has demonstrated promise in ameliorating EAE-induced cognitive and physical dysfunction in mice. It activates the PI3K/Akt signaling pathway while restraining the functionality of glycogen synthase kinase-3 beta (GSK-3β). These effects are critical for preventing neurodegeneration, boosting antioxidant defenses, and reducing neuroinflammation [ 262 ]. Notably, recent evidence from a comprehensive review highlights that GLP-1RAs promote myelinogenesis and myelin maintenance, with their beneficial effects potentially mediated through PI3K/AKT pathway activation [ 263 ]. Similarly, liraglutide has demonstrated neuroprotective effects against cuprizone-induced demyelination within an experimental model of MS established in mice through anti-inflammatory mechanisms, autophagy activation, NLRP3 inflammasome suppression, and anti-apoptotic processes. These effects might be facilitated via AMPK/Sirtuin 1 (SIRT1), autophagy, and the Toll-like receptor-4 (TLR-4)/NF-κB/NLRP3 signal transduction cascade [ 264 ]. Liraglutide did not significantly inhibit pyroptosis in BV2 cells in vitro, although its protective properties in a mouse model of EAE appear to be related to AMPK regulation, autophagy and inhibition of pyroptosis [ 265 ]. Among GLP-1RAs with notable neuroprotective potential, NLY01, a PEGylated form of exendin-4, has emerged as a long-acting agent. NLY01 led to a marked reduction in clinical scores and the frequency of relapses in a model of relapsing-remitting EAE [ 266 ]. CNS-infiltrating CD4 + T cells that secrete both IFN-γ and IL-17 A (Th1 and Th17) are crucial in the development of EAE [ 267 ]. Dulaglutide, another GLP-1RA, was found to suppress the proportion of pathogenic Th1 and Th17 cells and inhibit the secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) by Th1 cells within the CNS of EAE mice, resulting in improved clinical outcomes [ 268 ]. Additionally, microglia, which are primary targets of the GLP-1R signal transduction pathway in the spinal cord, exhibit reduced activation and decreased expression of pro-inflammatory cytokines following exendin-4 treatment, suggesting therapeutic potential in monophasic EAE [ 113 ].

The potential for GLP-1RAs to provide atheroprotective and antioxidant benefits in MS patients with high disease activity is also emerging, potentially reducing vascular risk [ 269 ]. In addition, a recent analysis of real-world data on MS patients has provided important insights concerning the employment of injectable GLP-1RAs, like semaglutide and tirzepatide, for the purpose of losing weight in overweight and obese populations. The findings indicate that GLP-1RAs are safe for MS patients, with tolerability comparable to that observed in the general population for this class of drugs [ 270 ]. Nevertheless, the exact function of GLP-1RAs in the treatment of MS has not been precisely determined and demands further exploration.

Intriguingly, recent studies have expanded the therapeutic scope of GLP-1RAs to neuroinflammatory regulation, with promising therapeutic potential observed in neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis [ 271 , 272 ]. A meta-analysis reported that T2DM patients treated with GLP-1RAs have a lower risk of Alzheimer’s disease than non-users (OR = 0.54, 95% CI, 0.30–0.96) [ 273 ]. Furthermore, A 36-week randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of NLY01 in patients with early, untreated Parkinson’s disease. Although NLY01 was not associated with any improvement in motor or non-motor features of Parkinson’s disease compared with placebo, subgroup analyses suggested a potential benefit in young participants with motor manifestations [ 274 ].

Sjögren’s syndrome

SS is a chronic autoimmune disorder that predominantly impacts the exocrine glandular system, particularly the lacrimal and salivary glands. The disease is characterized by progressive glandular hypoplasia, invasion of the affected lacrimal and salivary glands by CD4 + T cells, along the existence of anti-Ro/SSA antibodies in the serum [ 275 , 276 ]. The pathogenesis of SS is associated with immune cells including macrophages, monocytes, T lymphocytes, B lymphocytes and DCs [ 277 ]. While GLP-1RAs demonstrate immunomodulatory potential relevant to SS pathogenesis through their effects on key immune cell populations, direct experimental evidence characterizing their impact on SS-specific immune dysregulation remains strikingly limited. It is noteworthy that recent research has indicated that GLP-1RAs can regulate salivary gland epithelial cells, which play an essential role in the development of SS. Moreover, research has emphasized that apoptosis, lysosomal dysfunction, and altered autophagy are associated with salivary gland insufficiency and autoimmunity in SS [ 278 – 280 ].

GLP-1R is found on various cell types, and salivary gland epithelial cells are included [ 281 ]. Notably, GLP-1RA liraglutide has been proven to repair lysosomal function and boost lysosomal biogenesis in HFD mice and hepatocytes by activating the transcription factor EB (TFEB), which is a vital regulator of lysosomal function [ 282 ]. Additionally, lysosome-associated membrane protein 3 (LAMP3) is elevated within the salivary glands of specific individuals suffering from SS, and the resulting lysosomal dysfunction serves as a crucial factor in the evolution of the disease [ 280 ]. Overexpression of LAMP3 disrupts lysosomal membranes by degrading LAMP1, leading to lysosomal dysfunction and impaired autophagy [ 278 ]. GLP-1RA liraglutide treatment restored lysosomal function in LAMP3 overexpressing human salivary epithelial cell line A253 cells by reducing caspase-8 expression in vitro. They further demonstrated that GLP-1RA dulaglutide treatment restored lysosomal function in LAMP3 overexpressing mice, thereby preventing lysosomal membrane permeability and cell death in vivo [ 283 ]. Dry and pruritic skin is a common clinical manifestation of SS, with vasculitis being the second most common cutaneous manifestation, and histological examination usually confirms the diagnosis of leukocytoclastic vasculitis (LCV) [ 284 ]. Notably, a recent case report describes the first case of skin-restricted LCV induced 2 weeks after weekly subcutaneous semaglutide injections in a 73-year-old man with T2DM [ 285 ].

Systemic lupus erythematosus

SLE is an autoimmune disorder distinguished by nuclear autoantibodies, which can lead to the generation of immune complexes and inflammation in multiple organs [ 286 ]. Moreover, drug-induced lupus (DIL), with clinical manifestations similar to SLE, is an autoimmune phenomenon caused by exposure to certain drugs [ 287 ].

In a retrospective cohort study, GLP-1RAs exhibited a substantial decline in the occurrence rate of SLE in populations with T2DM and obesity [ 288 ]. However, a recently published case report demonstrated semaglutide-induced lupus erythematosus with multiple organ involvement [ 289 ]. Additionally, in recent post-marketing surveillance based on individual reports of adverse events while using semaglutide, 19 out of 28,954 (0.07%) reported SLE-like symptoms. This adverse effect was most common in women over 60 years of age, particularly those who had used the drug for less than 1 month [ 290 ]. Following the case report mentioned above, the safety profile of GLP1-RAs in patients with SLE has been questioned. Therefore, a recently initiated retrospective analysis to reassess the role of GLP1-RAs in SLE found that GLP1-RAs did not provoke the emergence of novel clinical manifestations of SLE and were correlated with a substantial decline in body mass index (BMI) [ 291 ]. As highlighted in a recent review, while GLP-1RAs show potential in treating SLE, further prospective investigations are needed to determine if they pose a risk of triggering autoimmune activity and whether their advantages in SLE outweigh such risks [ 292 ].

Currently, there are limited studies investigating the relationship between SLE and GLP-1RAs. The mechanisms and applications of GLP-1RAs in SLE remain largely unexplored, and their efficacy and safety need to be validated by further studies.

Discussion

In this review, we explore the roles of GLP-1R signaling in various immune cells, including macrophages, microglia, monocytes, granulocytes, CD4 + T cells, γδ T cells, i NKT cells, NK cells and ILCs (Fig.  2 ). We summarize the impact of GLP-1RAs on immune cell biology and discuss their potential contributions to autoimmune and autoinflammatory diseases by regulating immune responses (Table  2 ). Previous reviews, while exploring the impact of GLP-1RAs on immune and inflammatory diseases, have not established a connection between the regulatory roles of immune cells and the impact of the treatment on disease progression. The highlight of our work is to investigate immune cell biology directly and explore how GLP-1RAs influence disease by affecting the biological functions of relevant immune cells, providing important directions for future research.

Fig. 2 Roles of GLP-1R signaling in immune cell biology. The mechanism of action of the GLP-1R signaling pathway in macrophage, microglia, monocyte, neutrophil, eosinophil, T cell and its various subpopulations, and ILC is shown in the figure. Figure created with BioRender.com

Roles of GLP-1R signaling in immune cell biology. The mechanism of action of the GLP-1R signaling pathway in macrophage, microglia, monocyte, neutrophil, eosinophil, T cell and its various subpopulations, and ILC is shown in the figure. Figure created with BioRender.com

Table 2 Effect of GLP-1RAs treatment on autoimmune/autoinflammatory diseases autoimmune/autoinflammatory diseases Treatment Model Result Effect on immune system Reference Psoriasis Liraglutide Psoriasiform (imiquimod) db/db mice Liraglutide can improve psoriasis skin lesions of obese diabetic mice ↓ IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway [ 205 ] IBD Liraglutide DSS-induced colitis mice Liraglutide effectively alleviated DSS-induced colitis symptoms ↑ the release of IL-22 by ILC3s [ 185 ] RA Exenatide Lixisenatide Dulaglutide Human synoviocytes from RA patients exert significant protective effects against the progression of RA ↓ IL-1β, IL-6, IL-8, MCP-1, MMP, TNF-α, JNK, NF-kB [ 239 – 241 ] Asthma Liraglutide mouse asthma models may constitute a novel therapeutic approach for asthma ↓ IL-33, ↓ ILC2 expressing IL-5 and IL-13 [ 135 ] MS Liraglutide Semaglutide Dulaglutide EAE mice anti-inflammation and anti‐demyelination effect on EAE mice ↓ Th1, Th17, APC migration, IL-1β, IL-6, IL-17, TNF-α, NF-kB [ 262 , 264 , 268 ] SS Liraglutide A253 cells stably overexpressing LAMP3 Liraglutide can restore lysosomal function ↓ LAMP3 overexpression and cell death [ 283 ] db/db mice, diabetic mice; IBD, inflammatory bowel disease; DSS, dextran sulfate sodium; EAE, experimental autoimmune encephalitis; LAMP3, lysosome-associated membrane protein; RA, rheumatoid arthritis; MS, multiple sclerosis; SS, Sjögren’s syndrome

Table 2 Effect of GLP-1RAs treatment on autoimmune/autoinflammatory diseases autoimmune/autoinflammatory diseases Treatment Model Result Effect on immune system Reference Psoriasis Liraglutide Psoriasiform (imiquimod) db/db mice Liraglutide can improve psoriasis skin lesions of obese diabetic mice ↓ IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway [ 205 ] IBD Liraglutide DSS-induced colitis mice Liraglutide effectively alleviated DSS-induced colitis symptoms ↑ the release of IL-22 by ILC3s [ 185 ] RA Exenatide Lixisenatide Dulaglutide Human synoviocytes from RA patients exert significant protective effects against the progression of RA ↓ IL-1β, IL-6, IL-8, MCP-1, MMP, TNF-α, JNK, NF-kB [ 239 – 241 ] Asthma Liraglutide mouse asthma models may constitute a novel therapeutic approach for asthma ↓ IL-33, ↓ ILC2 expressing IL-5 and IL-13 [ 135 ] MS Liraglutide Semaglutide Dulaglutide EAE mice anti-inflammation and anti‐demyelination effect on EAE mice ↓ Th1, Th17, APC migration, IL-1β, IL-6, IL-17, TNF-α, NF-kB [ 262 , 264 , 268 ] SS Liraglutide A253 cells stably overexpressing LAMP3 Liraglutide can restore lysosomal function ↓ LAMP3 overexpression and cell death [ 283 ] db/db mice, diabetic mice; IBD, inflammatory bowel disease; DSS, dextran sulfate sodium; EAE, experimental autoimmune encephalitis; LAMP3, lysosome-associated membrane protein; RA, rheumatoid arthritis; MS, multiple sclerosis; SS, Sjögren’s syndrome

Effect of GLP-1RAs treatment on autoimmune/autoinflammatory diseases

Exenatide

Lixisenatide

Dulaglutide

Liraglutide

Semaglutide

Dulaglutide

db/db mice, diabetic mice; IBD, inflammatory bowel disease; DSS, dextran sulfate sodium; EAE, experimental autoimmune encephalitis; LAMP3, lysosome-associated membrane protein; RA, rheumatoid arthritis; MS, multiple sclerosis; SS, Sjögren’s syndrome

Presently, there is a scarcity of research on the effect of GLP-1RAs in autoimmune diseases such as ankylosing spondylitis (AS) and uveitis. However, extensive research has verified that GLP-1RAs exert anti-inflammatory actions in various tissues and organs by modulating inflammatory and immune responses (Fig.  3 ).

Fig. 3 Anti-inflammatory and immunomodulatory mechanisms of the GLP-1R signaling pathway. The figure illustrates the signaling pathways that can be initiated by GLP-1 and GLP-1RAs upon binding GLP-1R to exert anti-inflammatory effects and immunomodulatory effects. Figure created with BioRender.com

Anti-inflammatory and immunomodulatory mechanisms of the GLP-1R signaling pathway. The figure illustrates the signaling pathways that can be initiated by GLP-1 and GLP-1RAs upon binding GLP-1R to exert anti-inflammatory effects and immunomodulatory effects. Figure created with BioRender.com

Our review suggests that GLP-1RAs show potential for treating autoimmune and autoinflammatory diseases due to their anti-inflammatory and immunomodulatory properties. We elucidate that GLP-1RAs intervene with the pathogenic process of psoriasis at multiple targets by modulating the functions of T cells, keratinocytes and the expression of inflammatory factors. Nevertheless, there remains a dearth of pertinent research regarding the impacts of GLP-1RAs on Th17 cells and IL-23/IL-17 signaling axis, which are key in the etiology of psoriasis. Consequently, in the forthcoming period, it is imperative to conduct in-depth investigations into the specific molecular mechanisms underlying the anti-inflammatory and immunomodulatory properties of GLP-1RAs in psoriasis. Moreover, it is essential to more comprehensively examine the regulatory effects of GLP-1RAs on the cutaneous immune system. IBD is a heterogeneous disease and the response to GLP-1RAs may vary between patients, requiring individualized treatment strategies. The effect of combining GLP-1RAs with other drugs (e.g., biologics) for the treatment of IBD can be explored in the future.

In the patients with autoimmune/autoinflammatory diseases described in this review, co-morbidities such as metabolic syndrome and diabetes are often present. GLP-1RAs not only have the potential to treat the above-mentioned diseases but also ameliorate the co-morbidities simultaneously, which is important for patients with autoimmune/autoinflammatory diseases combined with metabolic diseases. However, this also makes it challenging to distinguish whether GLP-1RAs exert their effects by directly regulating immune cells or indirectly improving metabolic parameters. To better differentiate the mechanisms of GLP-1RAs, we propose recruiting more individuals who are of normal weight and do not have diabetes or obesity for future clinical trials. Additionally, in basic research, future studies could establish mouse models of obesity and diabetes and compare them with normal mice to exclude the interference of metabolic factors. This would enable us to explore and understand these mechanisms at a deeper level.

In addition, questions remain about the impact of GLP-1R signaling on immune cell biology and the precise role of GLP-1RAs in various autoimmune and autoinflammatory conditions. Key points for future research include the following. Firstly, the extent to which GLP-1R signaling regulates immune cell biology: are these signaling pathways primary mediators or co-participants in the immune response. Secondly, translation of laboratory findings into clinical practice: while some GLP-1RAs have shown promise in regulating immune responses in preclinical studies, clinical implementation remains a major challenge. Finally, exploring GLP-1R signaling in other immune cells: current research has focused on several immune cell types discussed in this review, but other immune cells also play crucial roles. Notably, understanding the complex regulatory network of GLP-1R signaling within various immune cells is essential.

Overall, GLP-1RAs represent a promising avenue for treating autoimmune and autoinflammatory diseases, though significant research gaps remain. Expanding clinical research and addressing these questions will be essential for fully realizing the therapeutic potential of GLP-1RAs.