title: Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice.
abstract: In type 1 diabetes (T1D), reactive oxygen species (ROS) and proinflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic β cells while promoting autoreactive T cell maturation. Superoxide-deficient nonobese diabetic mice (NOD.Ncf1(m1J)) are resistant to spontaneous diabetes, revealing the integral role of ROS signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-Mϕ) from NOD and NOD.Ncf1(m1J) mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-κB signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1(m1J) BM-Mϕ exhibited a 2- and 10-fold decrease in TNF-α and IFN-β proinflammatory cytokine synthesis, respectively, in contrast to NOD BM-Mϕ. Optimal expression of IFN-α/β is not solely dependent on superoxide synthesis, but requires p47(phox) to function in a NOX-independent manner to mediate type I interferon synthesis. Interestingly, MHC-II I-A(g7) expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-A(g7) downregulation. These findings suggest that defective innate immune-pattern-recognition receptor activation and subsequent decrease in TNF-α and IFN-β proinflammatory cytokine synthesis necessary for autoreactive T cell maturation may contribute to the T1D protection observed in NOD.Ncf1(m1J) mice.
authors.affiliation: Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Seleme
authors.forename: Weiqi
authors.initials: W
authors.lastname: Lei
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Burg
authors.forename: Kah Yong
authors.initials: KY
authors.lastname: Goh
authors.forename: Allison
authors.initials: A
authors.lastname: Metz
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D013481:Superoxides