T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 14; pp. 5295 - 5300
• Main Authors: Inoue, Makoto, Arikawa, Tomohiro, Chen, Yu-Hsun, Moriwaki, Yasuhiro, Price, Michael, Brown, Michael, Perfect, John R., Shinohara, Mari L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.04.2014; National Acad Sciences
• Subjects: Adipocytes; Animals; Antigens, CD - immunology; B lymphocytes; Biological Sciences; Cell Nucleus - metabolism; Cells; Cellular immunity; Cytokines; Down-Regulation; Endotoxemia; Gene expression; Immune system; Inflammation; Inflammation - immunology; Interleukin-1 Receptor-Associated Kinases - physiology; Interleukin-10 - physiology; Macrophages; Macrophages - immunology; Messenger RNA; Mice; Protein Transport; Ribonucleic acid; RNA; Sepsis; Signal Transduction; Simulation; Spleen; Sumoylation; T lymphocytes; T-Lymphocytes - immunology; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; CD154; CD40L; simultaneous stimulation; OPN; T cell migration
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1321427111

Endotoxemia is caused by excessive inflammation, but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia. A handful of reports have shown that innate immune responses are suppressed by the adaptive immune system. However, the molecular mechanism by which adaptive immune cells suppress innate inflammatory responses is not clear. Here, we report that T cells are shown to interact with macrophages at the early stage of enodotoxemia and to prolong survival of mice through controlling TNF and IL-10 levels by macrophage CD40 stimulation. The cross-talk between CD40 and toll-like receptor (TLR4) signaling first mediates IL-1 receptor-associated kinase 1 (IRAK1) nuclear translocation and its binding to the IL-10 gene promoter in macrophages, without interfering with the NFκB pathway. IL-10 is then detected by macrophages in an autocrine fashion to destabilize Tnfa mRNA. To induce IRAK1-mediated IL-10 expression, signals from both CD40 and TLR4 are essential. CD40 signaling induces IRAK1 sumoylation in the presence of TNF receptor-associated factor 2 (TRAF2) and intracellular isoform of osteopontin (iOPN) whereas TLR4 signaling provides IFN regulatory factor 5 (IRF5) as a chaperone for sumoylated IRAK1 nuclear translocation. Interaction of T cells with macrophages was observed in the spleen in vivo after endotoxemia induction with LPS injection. Our study demonstrates a mechanistic basis for the immunosuppressive role of macrophage CD40 in LPS endotoxemia.