title: Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.
abstract: T cell immunoglobulin mucin-3 (Tim-3) is an immune checkpoint inhibitor and its dysregulation has been related to T cell tolerance and many immune disorders, such as tumors and infection tolerance. However, the physiopathology roles of Tim-3 in innate immunity remain elusive. Here, we demonstrate that Tim-3 inhibits macrophage phagocytosis of L. monocytogenes by inhibiting the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway and increases bacterial burden. Tim-3 signaling promotes Nrf2 degradation by increasing its ubiquitination and, as a result, decreasing its nuclear translocation. CD36 and heme oxygenase-1 (HO-1), two downstream molecules in the Tim-3-Nrf2 signaling axis, are involved in the Tim-3- mediated immune evasion of L. monocytogenes both in vitro and in vivo. We here identified new mechanisms by which Tim-3 induces infection tolerance. By modulating the Tim-3 pathway, we demonstrate the feasibility of manipulating macrophage function as a potent tool for treating infectious diseases, such as Listeria infection.
authors.affiliation: Department of Biomedicine, Institute for Regeneration Medicine, Jilin University, Changchun 130021, China.|Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Zhiding
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biomedicine, Institute for Regeneration Medicine, Jilin University, Changchun 130021, China.
authors.forename: Dejun
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Guojiang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Shuaijie
authors.initials: S
authors.lastname: Dou
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Gencheng
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D008089:Listeria monocytogenes / Q000276:immunology* / Q000472:pathogenicity; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010587:Phagocytosis; D000067996:RAW 264.7 Cells; D015398:Signal Transduction
chemical_list: D018955:CD36 Antigens; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D051547:Heme Oxygenase-1