T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation.
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.
Department of Immunology, Department of Medicine, Division of Infectious Diseases, and Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710.
Makoto
M
Inoue
Tomohiro
T
Arikawa
Yu-Hsun
YH
Chen
Yasuhiro
Y
Moriwaki
Michael
M
Price
Michael
M
Brown
John R
JR
Perfect
Mari L
ML
Shinohara
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D007249:Inflammation / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D021381:Protein Transport; D015398:Signal Transduction; D058207:Sumoylation; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D015703:Antigens, CD; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse
CD154; CD40L; OPN; T cell migration; simultaneous stimulation