2. Academic Validation
  3. Siglec-H-/- Plasmacytoid Dendritic Cells Protects Against Acute Liver Injury by Suppressing IFN-γ/Th1 Response and Promoting IL-21+ CD4 T Cells

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

  • Cell Mol Gastroenterol Hepatol. 2024 Jun 6:101367. doi: 10.1016/j.jcmgh.2024.101367.
James Ahodantin 1,  Jiapeng Wu 2,  Masaya Funaki 3,  Jair Flores 3,  Xu Wang 4,  Pan Zheng 5,  Yang Liu 5,  Lishan Su 6
Affiliations

Affiliations

  • 1 Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: jahodantin@ihv.umaryland.edu.
  • 2 Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Microbiology and Immunology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
  • 3 Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
  • 4 Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
  • 5 OncoC4, Inc, Rockville, Maryland.
  • 6 Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Microbiology and Immunology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: lsu@ihv.umaryland.edu.
PMID: 38849082 DOI: 10.1016/j.jcmgh.2024.101367
Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Hepatic Tolerance; Inflammation; Plasmacytoid Dendritic Cells; Siglec-H.

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