Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced ImmunotoleranceSummary

Huiyuan Xie; Haiyan Deng; Xiaoping Yang; Xianxian Gao; Shanru Yang; Weiyi Chen; Yixuan Wang; Naibin Yang; Liang Yong; Xin Hou

Cellular and Molecular Gastroenterology and Hepatology (Jan 2024)

Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced ImmunotoleranceSummary

Huiyuan Xie,
Haiyan Deng,
Xiaoping Yang,
Xianxian Gao,
Shanru Yang,
Weiyi Chen,
Yixuan Wang,
Naibin Yang,
Liang Yong,
Xin Hou

Affiliations

Huiyuan Xie: Department of Laboratory Medicine, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
Haiyan Deng: Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
Xiaoping Yang: Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
Xianxian Gao: Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
Shanru Yang: Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
Weiyi Chen: Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
Yixuan Wang: Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
Naibin Yang: Department of Laboratory Medicine, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China; Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China; Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China; Department of Infection, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China; Laboratory of Stem Cell, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
Liang Yong: Department of Laboratory Medicine, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China; Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China; Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China; Department of Infection, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China; Laboratory of Stem Cell, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
Xin Hou: Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China; Correspondence Address correspondence to: Xin Hou, Ph.D. Health Science Center, Ningbo University, Ningbo, China, 818 Fenghua Road, Ningbo 315211, China.

Journal volume & issue: Vol. 18, no. 3
p. 101360

Abstract

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Background & Aims: The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV. Methods: We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA. Results: Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (ManfMye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in ManfMye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in ManfMye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice. Conclusion: The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8+ T cell exhaustion.

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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