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

Abstract

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.OPN | CD40L | CD154 | simultaneous stimulation | T cell migration

Cutting Edge: Role of Osteopontin and Integrin αv in T Cell–Mediated Anti-Inflammatory Responses in Endotoxemia

“…Although innate immune cells are equipped with intrinsic inhibitory mechanisms to negatively control inflammation in innate immunity (1-5), we and others found that adaptive immune cells also suppress early innate inflammatory responses during endotoxemia or sepsis (6-9). In our previous study (9), we demonstrated that T cells, but not B cells, are recruited in the splenic red pulp to interact with F4/80 + red pulp macrophages (RPMs) and suppress macrophage TNF expression by a direct T cell-macrophage interaction during LPS endotoxemia (9). Red pulp in the spleen is rich with RPMs, but has scarce T cells.…”

“…This suggested that even unprimed T cells play a critical role in immune responses to protect hosts from collateral damages by hyperinflammation. In the study, we further demonstrated a molecular mechanism downstream of macrophage CD40, through which TNF expression by macrophages is downregulated (9). CD40 signaling in macropahges induces IRAK1 sumoylation and nuclear translocation in the presence of TRAF2 (9).…”

“…In the study, we further demonstrated a molecular mechanism downstream of macrophage CD40, through which TNF expression by macrophages is downregulated (9). CD40 signaling in macropahges induces IRAK1 sumoylation and nuclear translocation in the presence of TRAF2 (9). Nuclear IRAK1 binds to the Il10 promoter in macrophages to induce expression IL-10, which reduces Tnfa mRNA stability to eventually downregulate TNFα production by macrophage (9).…”

“…Red pulp in the spleen is rich with RPMs, but has scarce T cells. Once the cell interaction occurs, CD40L on the T cell surface ligates CD40 on the macrophage cell surface to initiate anti-inflammatory responses during LPS endotoxemia (9). Because these responses occur before T cell priming, T cell cognate antigens are not necessary to achive the suppression.…”

The promotion of functional urinary bladder regeneration using anti-inflammatory nanofibers

“…In this specific setting, regulatory T-lymphocytes have been demonstrated to attenuate the inflammatory response following a major myocardial infarct in order to prevent unfavorable tissue remodeling events through pro-inflammatory cytokine inhibition of cardiomyocytes [49]. There is considerable functional overlap with regard to the role of T-lymphocytes in the inflammatory response [50–53]. However, in order to solely study the early innate immune response with regard to inflammation, we specifically chose the T-lymphocyte deficient animal model in order to gain better insight into the precise role this arm of the immune system may play without interference of the T-lymphocyte response.…”