Siglec-H-/- Plasmacytoid Dendritic Cells Protect Against Acute Liver Injury by Suppressing IFN-γ/Th1 Response and Promoting IL-21+ CD4 T Cells

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 18; no. 3; p. 101367
• Main Authors: Ahodantin, James, Wu, Jiapeng, Funaki, Masaya, Flores, Jair, Wang, Xu, Zheng, Pan, Liu, Yang, Su, Lishan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2024
• Subjects: Hepatic Tolerance; Inflammation; Plasmacytoid Dendritic Cells; Siglec-H; JNK; DAP12; ALT; MHC; BM; IHL; pDC-dAb; IFN; CXCL-10; BDCA2; Th; DCs; pDCs; CCR9; WT; Siglec-H; PBS; APCs; Plasmacytoid Dendritic Cells; IL; Siglec; KO; Inflammation; SOCS; STAT; Hepatic Tolerance; FLT3L; HA; ALF; ALI; PCR; ConA
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2024.101367

Siglec-H is a receptor specifically expressed in mouse plasmacytoid dendritic cells (pDCs), which functions as a negative regulator of interferon-α production and plays a critical role in pDC maturation to become antigen-presenting cells. The function of pDCs in autoimmune and inflammatory diseases has been reported. However, the effect of Siglec-H expression in pDCs in liver inflammation and diseases remains unclear. Using the model of concanavalin A–induced acute liver injury (ALI), we investigated the Siglec-H/pDCs axis during ALI in BDCA2 transgenic mice and Siglec-H-/- mice. Anti-BDCA2 antibody, anti-interleukin (IL)-21R antibody, and Stat3 inhibitor were used to specifically deplete pDCs, block IL21 receptor, and inhibit Stat3 signaling, respectively. Splenocytes and purified naive CD4 T cells and bone marrow FLT3L-derived pDCs were cocultured and stimulated with phorbol myristate acetate/ionomycin and CD3/CD28 beads, respectively. Data showed that specific depletion of pDCs aggravated concanavalin A–induced ALI. Remarkably, alanine aminotransferase, hyaluronic acid, and proinflammatory cytokines IL6 and tumor necrosis factor-α levels were lower in the blood and liver of Siglec-H knockout mice. This was associated with attenuation of both interferon-γ/Th1 response and Stat1 signaling in the liver of Siglec-H knockout mice while intrahepatic IL21 and Stat3 signaling pathways were upregulated. Blocking IL21R or Stat3 signaling in Siglec-H knockout mice restored concanavalin A–induced ALI. Finally, we observed that the Siglec-H-null pDCs exhibited immature and immunosuppressive phenotypes (CCR9LowCD40Low), resulting in reduction of CD4 T-cell activation and promotion of IL21+CD4 T cells in the liver. During T-cell-mediated ALI, Siglec-H-null pDCs enhance immune tolerance and promote IL21+CD4 T cells in the liver. Targeting Siglec-H/pDC axis may provide a novel approach to modulate liver inflammation and disease. [Display omitted]