title: Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation.
abstract: Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor-associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: George C
authors.initials: GC
authors.lastname: Brittain
authors.forename: Christine
authors.initials: C
authors.lastname: Stansberg
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Torkildsen
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002490:Central Nervous System / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D048008:TNF Receptor-Associated Factor 3; D051193:Toll-Like Receptors; D044767:Ubiquitin-Protein Ligases; C418046:Peli1 protein, mouse