| First Author | Seleme MC | Year | 2012 |
| Journal | Free Radic Biol Med | Volume | 52 |
| Issue | 9 | Pages | 2047-56 |
| PubMed ID | 22361747 | Mgi Jnum | J:183254 |
| Mgi Id | MGI:5318137 | Doi | 10.1016/j.freeradbiomed.2012.01.027 |
| Citation | Seleme MC, et al. (2012) Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice. Free Radic Biol Med 52(9):2047-56 |
| abstractText | In type 1 diabetes (T1D), reactive oxygen species (ROS) and proinflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic beta 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-Mvarphi) 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-kappaB signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1(m1J) BM-Mvarphi exhibited a 2- and 10-fold decrease in TNF-alpha and IFN-beta proinflammatory cytokine synthesis, respectively, in contrast to NOD BM-Mvarphi. Optimal expression of IFN-alpha/beta 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-alpha and IFN-beta proinflammatory cytokine synthesis necessary for autoreactive T cell maturation may contribute to the T1D protection observed in NOD.Ncf1(m1J) mice. |
