Innate immune cell LXR-β deficiency exacerbates hepatic injury and fibrosis in murine models of primary sclerosing cholangitis
10.1016/j.livres.2025.09.001
- Author:
Xiaohui FANG
1
;
Yang ZHANG
;
Junyao WANG
;
Yu ZHANG
;
Ziliang KE
;
Yiken LIN
;
Fangyuan CONG
;
Feng ZHANG
;
Jianhua ZHOU
;
Huiting SU
;
Shan CAO
;
Yulan LIU
;
Jun XU
Author Information
1. Department of Gastroenterology
- Keywords:
Liver X receptor beta(LXR-β);
Primary sclerosing cholangitis(PSC);
Innate immune cells;
Liver fibrosis;
LXR-β deficiency;
Nuclear receptor;
Bile acid receptor;
DDC-induced PSC
- From:
Liver Research
2025;9(3):239-248
- CountryChina
- Language:Chinese
-
Abstract:
Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-β in PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβ in the PSC model.Unexpectedly,Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2-/-DDC mice.However,Lxrβ depletion intensified DDC-induced PSC in the Rag2-/-mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2-/-DDC mice,Lxrβ-/-Rag2-/-DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.
