Investigating the Role of a Mast Cell-Specific Receptor in Sepsis-Associated Inflammation

PROJECT SUMMARY Sepsis is a life-threatening condition driven by an out-of-proportion inflammatory response to infection. Despite significant research efforts, current standard-of-care treatments, including antibiotics and fluids management, fail to address this underlying inflammatory dysregulation. Critically, no FDA-approved therapies specifically target sepsis-associated inflammation, underscoring a pressing unmet clinical need. Mast cells are widespread immune mediators of the innate immune system. Upon activation, they release inflammatory cytokines and recruit additional immune cells, amplifying the immune response. While traditionally linked to allergic diseases, recent studies indicate that depleting mast cells can reduce inflammation and improve outcomes in sepsis models. However, the molecular mechanisms behind this protective effect remain unclear. Our lab has identified Mas-related G-protein coupled receptor b2 (Mrgprb2) as a master regulator of mast cell function. Mrgprb2 enables mast cells to respond to danger signals and amplify inflammation after tissue injury. For instance, quorum-sensing molecules, released by bacteria during infection, bind Mrgprb2 on tissue-resident mast cells. Many endogenous Mrgprb2 agonists are upregulated during disease, contributing to pathological inflammation. Our preliminary data demonstrates that genetically inactivating Mrgprb2 in a mouse model of sepsis significantly reduces inflammation and mortality. Based on these findings, we hypothesize that Mrgprb2 activation in mast cells drives excessive inflammation during sepsis, exacerbating disease severity. To test this hypothesis, we will use the cecal slurry murine model, a well-established preclinical model that closely mimics human sepsis. Aim 1 will assess the role of Mrgprb2 in modulating sepsis severity by assessing clinical symptoms, bacterial clearance, and organ injury in the lungs and liver. Aim 2 will evaluate Mrgprb2-mediated mast cell activity during sepsis by measuring mast cell release products and immune cell recruitment. Aim 3 will identify and characterize the key endogenous Mrgprb2 activator contributing to inflammatory injury in sepsis. This research seeks to define the molecular pathways through which Mrgprb2 mediates sepsis-associated inflammation. Notably, several antagonists targeting MRGPRX2, the human ortholog of Mrgprb2, are currently in clinical trials, positioning our findings for rapid translation to patient care. By targeting Mrgprb2, this work holds the potential to reveal a novel therapeutic strategy that could revolutionize sepsis treatment.