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Quantitative assessment of innate myeloid cells in myelofibrosis: insights into myeloid and plasmacytoid dendritic cell depletion and disease progression.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, abnormal hematopoiesis, and extramedullary hematopoiesis. Abnormalities of the tumor microenvironment and immune system may be involved in the MF physiopathology and progression, particularly affecting innate myeloid cells (IMCs) such as myeloid dendritic cells (mDCs), plasmacytoid dendritic cells (pDCs) and monocytes. This study aims to quantitatively assess these cell populations in MF patients and their association with clinical outcomes. A cohort of 21 MF patients from the Universidade Federal de São…

Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors.

Chronic inflammation is a hallmark of impaired healing in a plethora of tissues, including skin, and is associated with aging and diseases such as diabetes. Diabetic chronic skin wounds are characterized by excessive myeloid cells that display an aberrant phenotype, partially mediated by stable intrinsic changes induced during hematopoietic development. However, the relative contribution of myeloid cell-intrinsic factors to chronic inflammation versus aberrant signals from the local environmental was unknown. Moreover, identification of myeloid cell intrinsic factors that contribute to chronic…

Mincle-dependent Th17 adjuvanticity requires TNFR1 signaling in myeloid cells.

Successful induction of protective T cells by recombinant protein vaccines requires adjuvants. The liposomal adjuvant system CAF01 induces r … ed conditional TNFR1-deficient mice to dissect cell type-specific contributions of TNF signaling in myeloid cells, DC and T cells to Th17 induction by the recombinant tuberculosis fusion protein H1 adjuvanted with CAF01. LysM-Cre-mediated deletion of TNFR1 on myeloid cells completely abrogated vaccine-induced Th17 differentiation, replicating the phenotype in m …

FTY720 Increases Doxorubicin Sensitivity in Resistant Acute Myeloid Leukemia Cells.

Chemoresistance remains a major barrier to effective treatment of acute myeloid leukemia, partly because resistant leukemic cells reduce intracellular drug exposure and evade apoptosis. FTY720, a sphingosine-1-phosphate receptor modulator, has reported antiproliferative and chemosensitizing activity in several tumor models. However, whether FTY720 increases doxorubicin sensitivity in doxorubicin-resistant acute myeloid leukemia cells, and whether this effect is associated with changes in drug-efflux transporters and protein kinase B/mechanistic target of rapamycin signaling, remains insufficie

Itraconazole induced ferroptosis in acute myeloid leukemia cells through TP53INP1.

BACKGROUND: Itraconazole (ITRA) is a broad-spectrum antifungal agent approved by the Food and Drug Administration (FDA). It has been shown to inhibit cancer growth, but the underlying molecular mechanism of itraconazole-induced cell death in acute myeloid leukemia (AML) remains largely elusive. METHODS: CCK-8 assay, colony-formation assay, flow cytometry, Western blotting, reactive oxygen species (ROS) detection, and ferroptosis analysis were performed to reveal the role and underlying mechanisms of itraconazole in AML cell lines. Itraconazole has also done research on in vivo experiments. R

MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.

Leukemic stem cells (LSC) are well recognized for their essential roles in acute myeloid leukemia (AML) initiation and relapse. LSC can be distinguished from non-LSC AML cells by the expression of specific cell surface markers, but there is considerable phenotypic heterogeneity among LSC in AML. Here, using primary patient samples, we report that mannose receptor C-type 2 (MRC2) can be used to enrich for LSC across various AML subtypes. When compared to MRC2- AML cells isolated from the same patient samples, MRC2+ leukemic subpopulations show increased in vitro clonogenic capacity, a stemness

TLR2 agonism suppresses myeloid leukemogenesis by reprogramming leukemia stem cells.

Patient adherence to treatment is an important factor in the effectiveness of antiretroviral regimens. Adherence to treatment could be monitored by estimation of antiretroviral drugs in biological fluids. We aimed to obtain information on the quantity and duration of excretion of lamivudine in urine following oral administration of a single dose of 300 mg and to assess its suitability for adherence monitoring purposes. Spot urine samples were collected before dosing and at 4, 8, 12, 24, 28, 32, 48, 72, and 96 hours post dosing from 10 healthy subjects, and lamivudine was estimated by high-pres

A role of arginase-1-expressing myeloid cells in cachexia.

BACKGROUND: Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, … ether, our findings point to a mechanism for cachexia which depends on expansion of ARG1-expressing myeloid cells, local restriction of arginine, loss of mitochondrial capacity and induced catabolism in skeletal muscle cells and in the heart.

Cervical mucosal inflammation expands functional polymorphonuclear myeloid-derived suppressor cells.

The mucosal immune system plays a fundamental role in maintaining microbial balance. Microbial imbalance in the female genital tract increases the risk for adverse health outcomes in women and may increase susceptibility to local infections. Myeloid-derived suppressor cells (MDSCs) remain understudied in the context of female genital tract conditions. Here we show that frequency of polymorphonuclear (PMN-) MDSCs increased in the cervical mucosa of women with Chlamydia trachomatis infection, bacterial vaginosis, or with a coinfection, but not in women with human papillomavirus infection. Mucosa

Вклад BTK, сигнализирующий в миелиоидных клетках, в нейроинфламмацию.

ВВЕДЕНИЕ: Тирозиновая киназа Брютона (ТБК) является членом семейства ТЭС, в котором имеются нерецепторные тиросиновые киназы, выраженные в клетках гематопоиетического происхождения, включая B лимфоциты и миэлоидные клетки. Выборочные ингибиторы BTK (BTKi) показали эффективность клинических испытаний при множественном склерозе (MS). Здесь мы изучили роль BTK в человеческих и мышиных миелиоидных клетках в исследованиях in vitro и vivo.МЕТОДЫ: Мы провели оценку i) воздействия ингибитора BTK (BTKi) evobrutinib на маркеры моноцитов для активации, кумуляции, сцепления и фагоцита в периферийных моноя

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INTRODUCTION: Bruton's tyrosine kinase (BTK) is a member of the TEC family of non-receptor tyrosine kinases expressed in cells of hematopoietic origin, including B lymphocytes and myeloid cells. Selective BTK inhibitors (BTKi) have shown efficacy in clinical trials in multiple sclerosis (MS). Here we investigated the role of BTK in human and mouse myeloid ce…

The role of myeloid derived suppressor cells in musculoskeletal disorders.

The immune system is closely linked to bone homeostasis and plays a pivotal role in several pathological and inflammatory conditions. Through various pathways it modulates various bone cells and subsequently sustains the physiological bone metabolism. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous immature myeloid-derived cells that can exert an immunosuppressive function through a direct cell-to-cell contact, secretion of anti-inflammatory cytokines or specific exosomes. These cells mediate the innate immune response to chronic stress on the skeletal system. In chronic

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… However, they also share immune regulatory features with mature myeloid cells that support the inflammatory environment. … This effect may be caused by selecting MDSCs using Gr-1 and CD11b which can also be found on potentially proinflammatory mature myeloid cells. …

Leukemic stem cells and therapy resistance in acute myeloid leukemia.

A major obstacle in the treatment of acute myeloid leukemia (AML) is refractory disease or relapse after achieving remission. The latter arises from a few therapy-resistant cells within minimal residual disease (MRD). Resistant cells with long-term self-renewal capacity that drive clonal outgrowth are referred to as leukemic stem cells (LSC). The cancer stem cell concept considers LSC as relapse-initiating cells residing at the top of each genetically defined AML subclone forming epigenetically controlled downstream hierarchies. LSC display significant phenotypic and epigenetic plasticity, par

Myeloid-derived suppressor cells: A new emerging player in endometriosis.

Endometriosis is a common gynecological disorder defined by the presence of endometrial tissue outside the uterus. This is commonly associated with chronic pelvic pain, infertility, and dysmenorrhea, which occurs in approximately 10% of women of reproductive age. Although the exact mechanism remains uncertain, it has been widely accepted to be an estrogen-dependent and inflammatory disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells with immunosuppressive capacity and non-immunological functions. They have been found to be aggressively involved in the pa

Emerging avenues linking myeloid-derived suppressor cells to periodontal disease.

Periodontal disease is one of the most common inflammatory disorders in humans. Gingivitis is the mildest form of periodontal disease and its progression can lead to periodontitis, an inflammatory disease characterized by soft tissue damage that can lead to progressive destruction of the periodontal ligament and alveolar bone. Diverse populations of immune cells are involved in periodontal disease. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells derived from hematopoietic precursor cells and exhibit T cell immunosuppressive functions that are …

Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors.

Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a G0 marker (G0M), we narrow down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis reveals NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by inhibitors of interleukin-1 receptor-associated kinase 1/4 (IRAK1/4 inhibitors) to

HSP90α induces immunosuppressive myeloid cells in melanoma via TLR4 signaling.

BACKGROUND: Tumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors. Their interactions with myeloid cells lead to the generation of myeloid-derived suppressor cells (MDSC), which inhibit the antitumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced immunosuppressive activity via increased expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90α (HSP90α) in EV. Here, we investigated whether soluble HSP90α could convert monocyte…

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, … , which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of periphera …

Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) belongs to a group of hematological cancer whose relapse cases are often associated with chemoresistance that impairs treatment success and contributes to a poor outcome. For this reason, there is an urgent need for the development of new therapeutic strategies. Herein, we explore the combination of venetoclax, a BCL2 inhibitor, and embelin, an XIAP inhibitor, in the AML cell lines. Combinatory treatment of venetoclax and embelin potentiated cytotoxic effects of these drugs, demonstrating that both in combination present lower IC50 values than single treatment of e

Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling.

Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell-specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that c