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

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

Cellular and Molecular Gastroenterology and Hepatology (Jan 2024)

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

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

Affiliations

James Ahodantin: 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; Correspondence Address correspondence to: Correspondences. James Ahodantin, PhD, Institute of Human Virology, Division of Virology, Baltimore, Maryland 21201-1544.
Jiapeng Wu: 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
Masaya Funaki: 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
Jair Flores: 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
Xu Wang: Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
Pan Zheng: OncoC4, Inc, Rockville, Maryland
Yang Liu: OncoC4, Inc, Rockville, Maryland
Lishan Su: 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; Lishan Su, PhD, Institute of Human Virology, Universtiy of Maryland School of Medicine, Baltimore, Maryland 21201-1544.

Journal volume & issue: Vol. 18, no. 3
p. 101367

Abstract

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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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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