Innate immune cell LXR-β deficiency exacerbates hepatic injury and fibrosis in murine models of primary sclerosing cholangitis

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.

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

Authors’ contributions

Xiaohui Fang: Writing - review & editing, Writing - original draft, Visualization, Validation, Software, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yang Zhang: Writing - original draft, Visual-ization, Validation, Software, Resources, Methodology, Investi-gation, Formal analysis, Data curation. Junyao Wang: Writing -original draft, Visualization, Validation, Software, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yu Zhang: Writing - review & editing, Re-sources, Methodology, Data curation. Ziliang Ke: Writing - re-view & editing, Resources, Methodology, Data curation. Yiken Lin: Writing - review & editing, Resources, Methodology. Fan-gyuan Cong: Writing - review & editing, Resources, Methodol-ogy. Feng Zhang: Writing - review & editing, Resources, Methodology. Jianhua Zhou: Writing - review & editing, Re-sources, Methodology. Huiting Su: Writing - review & editing, Resources, Methodology. Shan Cao: Writing - review & editing, Supervision, Project administration, Methodology, Conceptuali-zation, Funding acquisition. Yulan Liu: Writing - review & edit-ing, Supervision, Project administration, Methodology, Funding acquisition, Conceptualization. Jun Xu: Writing - review & edit-ing, Supervision, Project administration, Methodology, Funding acquisition, Conceptualization.

Data availability statement

The data contained in this manuscript or supplementary ma-terial will be made available upon request from the corresponding authors.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (No. 82370555 to Jun Xu, and No. 82370537 and No. 82341228 to Yulan Liu), the Capital Health Research and Development of Special (No. CFH2024-1-4081 to Yulan Liu, and No. CFH2024-4-4089 to Jun Xu), the Beijing Municipal Natural Science Foundation (No. 7232196 to Yulan Liu), and Peking Uni-versity People's Hospital Scientific Research Development Funds (No. RDJP2023-22 to Jun Xu and No. RDGS2024-02 to Shan Cao). We extend our sincere appreciation to the personnel of the Insti-tute of Clinical Molecular Biology & Central Laboratory at Peking University People's Hospital for their invaluable technical assistance.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2025.09.001.

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