CD40 ligation by T cells downregulates macrophage TNF production by IRAK1-mediated IL-10 expression and controls innate hyperinflammation (INM9P.462)

Abstract

Abstract Endotoxemia is caused by excessive inflammation, but immune system has various mechanisms to avoid collateral organ damages 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 found that T cell-macrophage interaction prolonged survival of mice in lipopolysaccharide (LPS)-induced enodotoxemia through controlling TNF levels, demonstrated by T cell reconstitution in Rag2-deficient recipients. Downregulation of macrophage TNF expression was achieved by crosstalk between CD40 and TLR4 signaling pathways, which mediated IRAK1 nuclear translocation and its binding to the Il10 promoter in macrophages, without interfering the NFκB pathway. IL-10 is then detected by macrophages in an autocrine fashion to destabilize Tnfa mRNA, resulting in attenuated TNF levels. Simultaneous stimulation of CD40 and TLR4 signaling pathways was essential to induce IRAK1-mediated IL-10 expression; because CD40 signaling licenses IRAK1 nuclear translocation by IRAK1 sumoylation in the presence of TRAF2 and intracellular isoform of osteopontin (iOPN), while TLR4 signaling provides IRF5 as a chaperone of sumoylated IRAK1 for its nuclear translocation. Our study demonstrates a mechanistic basis of the immunosuppressive role of macrophage CD40 in LPS endotoxemia.