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

James Ahodantin; Jiapeng Wu; Masaya Funaki; Jair Flores; Xu Wang; Pan Zheng; Yang Liu; Lishan Su

doi:10.1016/j.jcmgh.2024.101367

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

Cell Mol Gastroenterol Hepatol. 2024;18(3):101367. doi: 10.1016/j.jcmgh.2024.101367. Epub 2024 Jun 6.

Authors

James Ahodantin¹, Jiapeng Wu², Masaya Funaki³, Jair Flores³, Xu Wang⁴, Pan Zheng⁵, Yang Liu⁵, Lishan Su⁶

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: [email protected].
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: [email protected].

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 (CCR9^LowCD40^Low), 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.

MeSH terms

Animals
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Chemical and Drug Induced Liver Injury / immunology
Chemical and Drug Induced Liver Injury / metabolism
Chemical and Drug Induced Liver Injury / pathology
Concanavalin A / pharmacology
Dendritic Cells* / immunology
Dendritic Cells* / metabolism
Disease Models, Animal
Interferon-gamma* / metabolism
Interleukin-21
Interleukins* / metabolism
Liver / immunology
Liver / metabolism
Liver / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout*
STAT3 Transcription Factor / metabolism
Sialic Acid Binding Immunoglobulin-like Lectins / genetics
Sialic Acid Binding Immunoglobulin-like Lectins / metabolism
Signal Transduction
Th1 Cells / immunology

Substances

Concanavalin A
Interferon-gamma
Interleukin-21
Interleukins
STAT3 Transcription Factor
Sialic Acid Binding Immunoglobulin-like Lectins

Abstract

MeSH terms

Substances

Grants and funding