Mechanisms of mast cell activation and function in natural immunity to bacteria

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Recent studies indicate that mast cells (MCs), key contributors to the pathology and mortality associated with anaphylaxis and other allergic disorders, can also promote health by participating in natural immune responses to bacterial infections. Using genetically MC-deficient KitW/KitW-v-mice, we and others have shown that the activation of MCs, i.e. by complement components, is essential for mounting protective host defence in acute septic peritonitis induced by cecal ligation and puncture (CLP), in part because MCs recruit circulating leukocytes with bactericidal properties. Yet, it remains largely unclear 1) how MCs are activated and 2) how MCs provide protection of the host in the context of innate immune responses. Endothelin-1 (ET-1), a potent vasoconstrictor and MC secretagogue, contributes significantly to morbidity and mortality of septic peritonitis and ET-1 levels in the peritoneum are greatly increased in KitW/ KitW-v-mice after CLP. We hypothesize that 1) ET-1 activates MCs and that 2) MCs regulate ET-1 levels and toxicity at sites of bacterial infection by facilitating degradation, binding, and/or clearance of ET-1. To test these hypotheses, we will combine genetic approaches using ET-1 receptor deficient MCs, derived from ETA-/- and ETB-/- embryonic stem cells, adoptive transfer techniques, involving KitW/KitW-v-mice and "MC knock-in mice", and highly relevant in vivo models, including CLP. Protective natural immune responses can be enhanced by upregulating MC numbers and/or function. Our studies may extend this potential therapeutic strategy by identifying novel underlying mechanisms of MC activation and/or effector functions in innate immune responses to bacteria.