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Abstract

Chronic liver diseases such as alcoholic liver disease (ALD) and metabolic dysfunction–associated steatotic liver disease (MASLD; formerly non-alcoholic fatty liver disease, NAFLD) are major global health burdens, often progressing to steatohepatitis, fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. While the role of myeloid cells in liver pathology is well established, the contribution of innate lymphoid cells (ILCs) remains poorly understood. ILCs are tissue-resident immune cells that rapidly produce cytokines and regulate inflammation and tissue remodeling. In this thesis, I established a physiologically relevant murine model combining chronic alcohol intake with a saturated fat diet (SFD -ALC), which mimics dietary and metabolic risks in human liver disease. This model recapitulates progressive liver pathology: steatosis by week 3, steatohepatitis by week 6, fibrosis by week 9, and cirrhosis with prolonged treatment. Using this model, I showed that RAG1-knockout mice, lacking adaptive immunity, developed steatohepatitis and fibrosis whereas NSG mice that are deficient in all lymphocytes developed steatosis but not hepatitis or fibrosis, implicating a critical role of ILCs in disease progression. The ILC3-deficient RORγt-KO mice, treated with SFD-ALC, developed steatohepatitis and fibrosis comparable to wild type mice, while IL-7R-cKO mice, deficient in ILC2s and partially deficient in ILC1s/ILC3s, did not develop steatohepatitis and fibrosis. Therefore, ILC1s and/or ILC2s likely drive the disease progression. Single-cell RNA sequencing revealed three ILC1 subsets. IL-18R⁺ ILC1 subset expands after SFD-ALC treatment whereas this expansion was reduced in IL-7R-cKO mice. Depletion of NK1.1⁺ cells reduced neutrophil infiltration, supporting ILC1 involvement in hepatitis. Spatial transcriptomics revealed proximity between ILC1s and Kupffer cells (KCs), with increased IL-15 expression in KCs after 3 weeks of SFD-ALC treatment, suggesting that IL-15-mediated ILC1 activation drives inflammation. IL-7R-cKO mice also showed reduced Tgfb1 expression in KCs and lower collagen deposition, suggesting that ILC2-derived IL-13 promotes fibrosis by inducing pro-fibrotic polarization of KCs. Together, these findings highlight distinct roles for ILC1s and ILC2s in chronic liver disease.