Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice

Academic Article


  • 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 ) 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 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 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 to function in a NOX-independent manner to mediate type I interferon synthesis. Interestingly, MHC-II I-A expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-A 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 mice. © 2012 Elsevier Inc. All rights reserved. m1J m1J m1J phox g7 g7 m1J
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    Author List

  • Seleme MC; Lei W; Burg AR; Goh KY; Metz A; Steele C; Tse HM
  • Start Page

  • 2047
  • End Page

  • 2056
  • Volume

  • 52
  • Issue

  • 9