title: Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease.
abstract: T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti-IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl(2)MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3(+) NKT cells are in an activated state, and Gal-9 directly induces Tim-3(+) NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3-expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9-signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD.
authors.affiliation: Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Tang
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liang
authors.forename: James
authors.initials: J
authors.lastname: Potter
authors.forename: Xuan
authors.initials: X
authors.lastname: Jiang
authors.forename: Hai-Quan
authors.initials: HQ
authors.lastname: Mao
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D037161:Galectins / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006706:Homeostasis / Q000276:immunology*; D019409:Interleukin-15 / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D011991:Receptors, Virus / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D019409:Interleukin-15; D011991:Receptors, Virus; C508186:galectin 9, mouse