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Hepatocyte DAX1 Deletion Exacerbates Inflammatory Liver Injury by Inducing the Recruitment of CD4+ and CD8+ T Cells through NF-κB p65 Signaling Pathway in Mice

Authors :
Hyo-Jeong Yun
Young-Joo Suh
Yu-Bin Kim
Eun-Jung Kang
Jung Hyeon Choi
Young-Keun Choi
In-Bok Lee
Dong-Hee Choi
Yun Jeong Seo
Jung-Ran Noh
Hueng-Sik Choi
Yong-Hoon Kim
Chul-Ho Lee
Source :
International Journal of Molecular Sciences, Vol 23, Iss 22, p 14009 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Fulminant hepatitis is characterized by rapid and massive immune-mediated liver injury. Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1; NR0B1) represses the transcription of various genes. Here, we determine whether DAX1 serves as a regulator of inflammatory liver injury induced by concanavalin A (ConA). C57BL/6J (WT), myeloid cell-specific Dax1 knockout (MKO), and hepatocyte-specific Dax1 knockout (LKO) mice received single intravenous administration of ConA. Histopathological changes in liver and plasma alanine aminotransferase and aspartate aminotransferase levels in Dax1 MKO mice were comparable with those in WT mice following ConA administration. Unlike Dax1 MKO mice, Dax1 LKO mice were greatly susceptible to ConA-induced liver injury, which was accompanied by enhanced infiltration of immune cells, particularly CD4+ and CD8+ T cells, in the liver. Factors related to T-cell recruitment, including chemokines and adhesion molecules, significantly increased following enhanced and prolonged phosphorylation of NF-κB p65 in the liver of ConA-administered Dax1 LKO mice. This is the first study to demonstrate that hepatocyte-specific DAX1 deficiency exacerbates inflammatory liver injury via NF-κB p65 activation, thereby causing T-cell infiltration by modulating inflammatory chemokines and adhesion molecules. Our results suggest DAX1 as a therapeutic target for fulminant hepatitis treatment.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
23
Issue :
22
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.06dea51e90a34a03bffdc8a7e63d9ae4
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms232214009