Metabolism: clinical and experimental · 2025
DC-SIGN+ macrophages alleviate metabolic dysfunction-associated steatotic liver disease via fine-tuning TLR4 signaling and inflammatory secretory profiles.
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Liu Jinxia, Wu Haifeng, Zhou Ling, Jin Qin, Ji Huoyan, Hu Baoying, Wu Hongpei, Chen Ting, Wang Xun, Hong Jianwei, Feng Rongwei, Zhang Xiaojun, Zhou Jiali, Zhang Weiliang, Wang Xu, Qu Lishuai, Wan Chunhua
Аннотация
BACKGROUND & AIMS: Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression.
METHODS: DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human DC-SIGN (hDC-SIGN) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion.
RESULTS: DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of CD68 promoter-specific hDC-SIGN markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, LewisX (LeX)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion.
CONCLUSIONS: DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.
METHODS: DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human DC-SIGN (hDC-SIGN) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion.
RESULTS: DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of CD68 promoter-specific hDC-SIGN markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, LewisX (LeX)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion.
CONCLUSIONS: DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.