Resolution of neutrophil response for effective T cell functions and tissue repair

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PROJECT SUMMARY/ABSTRACT – PROJECT 1 Migration of neutrophils to sites of tissue infection is vital for pathogen clearance and, thus, host survival. Importantly, once they complete their action, infiltrated neutrophils during the early infection phase should quickly initiate spontaneous apoptosis. A delayed neutrophil resolution is often associated with widespread tissue damage, organ failure, and ultimately death in severely infected patients. Therefore, the presence of unresolved neutrophil response during infection has long been believed to be detrimental, making it more difficult for patients to recover. Although growing evidence now suggests that neutrophils not only contribute to the tissue damage, but also orchestrate T cell functions and tissue repair, it has been challenging to clearly differentiate host-protective roles of neutrophils from their damaging inflammatory functions because most of the studies used over-activated or inappropriate inflammatory responses, which fail to restore tissue homeostasis. Therefore, the contribution of neutrophils to the host immune response and tissue repair may not be properly evaluated in these models. We undertook this study to address critical knowledge gaps regarding the function and fate of neutrophils during the infection. Through several lines of evidence from our preliminary study using a fully recovering mouse influenza infection model, we propose novel functions of neutrophil that can actively promote tissue healing and the resolution of inflammation. We discovered that apoptotic neutrophils actively engage with the proliferation and survival of other surrounding cells (e.g., epithelial cells and macrophages). This mitogenic and pro-survival effect of apoptotic neutrophils was mainly mediated by the secretion of epidermal growth factor (EGF). Moreover, live intravital multiphoton microscopy (IV-MPM) of our newly generated Ly6GCre/ROSAtdTomato/Csf1r-EGFP mice revealed a striking motility pattern of neutrophils and their phagocytes during the resolution phase within the infected airway, which may represent additional beneficial functions of neutrophils in protecting the host against infections. We hypothesize that resolution of neutrophil response during influenza infection is not merely a passive termination of the early neutrophil infiltrates but rather an active biochemical and cellular process to establish effective T cell immune responses while enabling tissues to repair and return to normal function. We will test the hypothesis that (1) apoptotic neutrophils promote tissue repair and (2) neutrophils control their own clearance. We will also determine (3) whether neutrophil resolution regulates T cell functions and memory formation. Given the important immune- modulatory properties of neutrophils, understanding of novel functions of neutrophil during the resolution of inflammation could be harnessed to combat infection and chronic inflammatory conditions.