Inhibition of damage-mediated interleukin-1β and interleukin-18 secretion by short chain fatty acids (SCFAs)

点击翻译按钮获取中文摘要

Extracellular ATP serves as a ”danger signal” indicating cell damage and induces the secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 by monocytes, macrophages and epithelial cells. These cytokines play a crucial role in host defense against pathogens. An increased and uncontrolled cytokine release, however, contributes to the pathogenesis of systemic inflammation, a frequent and life-threatening complication after severe trauma, major surgery, or ischemia/reperfusion injury. Because no effective therapies are currently available, the mortality in patients is still unacceptably high. Therefore, it is of high clinical interest to develop therapeutic approaches that control the damage-mediated cytokine-release while sparing defense against infections. This project aims to characterize an anti-inflammatory mechanism activated by short chain fatty acids (SCFAs) that inhibits the ATP-mediated release of IL-1β and IL-18. SCFAs are produced and secreted by certain gut bacteria during fermentation of carbohydrates. In unpublished pilot experiments, SCFAs and synthetic agonists of the SCFA receptors efficiently inhibited the ATP-induced IL-1β and IL-18 release by monocytes, macrophages and colon epithelial cells but did not prevent ATP-independent cytokine release in response to a bacterial toxin. Surprisingly, this anti-inflammatory effect seems to be mediated by both, SCFA receptors and nicotinic acetylcholine receptors (nAChRs). From the traditional view, nAChRs function as ligand-gated ion channels allowing neurotransmission. In previous studies, however, I was able to show, that activation of nAChRs in monocytes induces a metabotropic, anti-inflammatory signal transduction pathway. I assume that this also applies to SCFAs. This results in a completely new therapeutic approach for damage-mediated sterile inflammation. The aims of this project are to elucidate: 1. if SCFAs inhibit the ATP-induced inflammasome activation and cytokine release in primary human monocytes, macrophages, and colonic epithelial cells; 2. the signal transduction pathways translating the presence of SCFAs into a metabotropic signal at nAChRs to inhibit ATP-induced cytokine-release; 3. if this mechanism is active in vivo and, thus, has the potential to enter the clinical arena for the prevention of sterile inflammation. This project will characterize a novel SCFA-induced anti-inflammatory mechanism and will test its effectiveness in vivo. The results obtained within this project will open new pioneering therapeutic options for sterile, systemic inflammation. Moreover, this project is intended to create the basis for a clinically oriented follow-up project.