The role of complement and Toll-like receptors in sterile inflammation.
Sterile inflammation is similar to non-sterile inflammation, but there are no exgenous stimuli present. It is induced by "damaged self" typically like in ischemia-reperfusion injury. The mechanisms leading to sterile inflammation is like the non-sterile, mediated by innate immunity including the complement systems and the TLRs. Complement and the Toll-like receptors (TLR) are two main pattern recognition systems initiating host protection. However, if improperly activated, they might induce a sterile inflammation and tissue damage, like in trauma and cardiovascular diseases. TLRs and complement are closely cross-taking, implying synergist inflammatory effects. This has led us to search for key “bottle-neck” upstream molecules in both systems that could be targets for inhibition, opposed to a more traditional way of inhibiting innate immunity by blocking a single downstream inflammatory molecule, e.g. a cytokine. C3 and C5 are central molecules for all complement pathways, and CD14 is an important co-receptor for a number of TLRs, including TLR2 and TLR4. So far, we have documented that combined inhibition of complement and CD14 abolished bacteria-induced inflammatory responses ex vivo in human whole blood, and markedly attenuated the cytokine storm and improved survival in mice and pig polymicrobial sepsis. In this project we aim to test the hypothesis that such combined inhibition can be applied to dampen the sterile inflammation induced by endogenous danger signals. We have recently produced C3/CD14 double-knock-out mice which will be tested together with single knock-outs and wild type animals in established models of blunt chest trauma and heart failure. The results will have consequences for future therapeutic strategies in inflammatory diseases where complement and TLRs paly a pathogenic role. The postdoc candidate started medio December 2016 and thus no scientific results have been obtain and can be reported.