Itaconate inhibits CD103+ TRM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis

Abstract

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8+ T cells (TRM). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic TRM. Approach and Results: The numbers of intrahepatic CD103+ TRM were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic TRM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103+ TRM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103+ TRM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103+ TRM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8+T cells. Moreover, 4-OI reduced intrahepatic CD103+ TRM and ameliorated liver injury in murine models of PSC. Conclusions: Itaconate exerted immunomodulatory activity on CD103+ TRM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103+ TRM with itaconate has therapeutic potential in PSC.