Targeting the CHRNA7 Receptor to Modulate Wound Antimicrobial Responses

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#7 PROJECT SUMMARY Skin wound bacterial infections pose a significant health care burden in the US. They are frequently caused by Staphylococcus aureus and can be worsened by secondary complications like bacteremia. Of note, males have a 2-fold higher incidence of S. aureus infection than females in the US. While the higher susceptibility to S. aureus infection in males can also be observed in mice, reasons for this sex dimorphism are not well defined. What is known is that optimal host responses to wound infection need balanced pro- and anti- inflammatory signals by skin and resident immune cells. For example, neutrophil influx to help clear infections is facilitated by Toll-like receptor (TLR)-dependent pro-inflammatory cytokines and antimicrobial peptide (AMP) secretion by keratinocytes. Consequently, dysregulation or sex dimorphisms of any these host responses would negatively affect wound infection outcomes. In fact, our lab has established in the last several years that overactivation of the nicotinic acetylcholine receptor (nAChR) subtype CHRNA7 may play a prominent role in impairing the host defense against skin infection in mice and humans by lowering TLR2-mediated inflammation, AMP production, and neutrophil influx to the wound infection site. However, the relative contribution of keratinocyte CHRNA7 vs. immune cell CHRNA7 to this host response suppression is unknown. We have also not elucidated the CHRNA7-dependent downstream signaling mechanism(s) leading to the above phenotypes and not examined sex dimorphisms in CHRNA7 responses in the context of skin inflammation and wound infection. In this proposal, we will address two specific aims. 1) We will test our hypotheses that keratinocyte CHRNA7 is a major player in dampening wound antimicrobial responses and immune cell recruitment in a sex specific manner, which is supported by our pilot data. 2) We will elucidate the signaling mechanisms by which keratinocyte CHRNA7 impairs TLR2-mediated the production of immunomodulatory factors that are necessary for downstream neutrophil antimicrobial responses in vitro. Our studies will begin to unravel a fundamentally new mechanism by which keratinocyte CHRNA7 modulates wound antimicrobial responses in a sex specific manner and may be the basis for establishing CHRNA7 as a novel target for pharmacologic interventions that are designed to improve wound healing outcomes in both men and women.