Immunosuppression by leukocyte ADAM17 during sepsis

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SUMMARY. Sepsis - a severe systemic inflammatory response to bacterial infection - is currently the tenth most common cause of death in the United States and the primary cause of death from infection in hospitals. Despite advances in supportive care and disease-specific treatments, the incidence of sepsis and the costs associated with its treatment are rising, and are predicted to increase further as the population ages. Targeting the inflammatory phase of sepsis has failed to improve survival and there is a need for new therapeutic strategies. Increasing evidence supports a central role for immunosuppression in sepsis, which enhances the opportunity for prolonged and secondary infections. For instance, impairment of neutrophil recruitment, the first leukocyte population to respond during bacterial infection, is a critical hallmark of sepsis and is directly related to the severity of the disease. At this time, a deeper understanding of the molecular mechanisms underlying neutrophil dysfunction during sepsis is needed. Our long-term goal is to bolster the neutrophil response during sepsis, especially in light of increasing bacterial resistance to antibiotics. Our research group, which provides broad expertise in leukocyte effector activities, has determined that the membrane-associated metalloprotease ADAM17 in leukocytes is an important gatekeeper of neutrophil infiltration into sites of infection. For instance, gene-targeting ADAM17 in mouse leukocytes was found to accelerate neutrophil recruitment and bacterial clearance, and significantly improve survival during sepsis. The central hypothesis of our proposal is that over-activation of ADAM17 during sepsis promotes neutrophil dysfunction. The objective of our study is to determine the mechanism by which ADAM17 regulates neutrophil recruitment and to assess the protease as a drug target for sepsis. Our preliminary findings reveal for the first time that the chemokine receptor CXCR2 in neutrophils, which directs their migration into sites of infection, is cleaved by ADAM17 upon cell activation and that the surface expression levels of CXCR2 on circulating neutrophils are down-regulated by ADAM17 during sepsis. The specific aims of this R21 (exploratory/developmental) proposal are to establish the role of CXCR2 shedding by ADAM17 in regulating neutrophil recruitment following cecal ligation and puncture, a model of acute polymicrobial sepsis (Aim 1). In addition, we will evaluate ADAM17 as a drug target for sepsis (Aim 2). Resources unique to our study include conditional ADAM17 knockout mice and highly selective and potent ADAM17 inhibitors. The impact of our study is that it pursues a novel angle for developing therapeutic targets to improve survival by septic patients. If successful, our study will provide new information to advance our understanding of the mechanisms of action of ADAM17 during sepsis and establish its therapeutic potential.