Chemokine receptor signaling and the dynamics of neutrophil phenotypes during inflammatory lung injury

PROJECT SUMMARY / ABSTRACT Neutrophils are essential for host defense during bacterial infections, but their excessive activation can also promote tissue injury. Recent studies suggest that there are distinct subsets or states of neutrophils that allow them to engage in both exacerbation of inflammatory injury as well as repair and regeneration during the post-injury phase. Chemokine receptors such as CXCR2 and CXCR4 are expressed differentially on selected neutrophil subpopulations and are thought to regulate the trafficking of neutrophils between the bone marrow and the tissues during acute infections. However, the precise dynamics of how distinct neutrophil subpopulations are trafficked and how they contribute to discrete phases during lung injury and repair remain unclear. Identifying the distinct roles of CXCR2 and CXCR4 receptor signaling would allow for precision therapeutic targeting of neutrophil subpopulations in order to allow for their necessary host defense function during lung injury, minimize tissue injury caused by maladaptive neutrophil subpopulations and also enable resolution and repair of lung tissue in the post-acute phase. We have designed novel peptides that allosterically target CXCR2 and CXCR4, and our Supporting Data also suggest novel molecular mechanisms by which these chemokine receptors signal. We have furthermore studied phenotypes of activated neutrophils and assessed the dynamics of distinct neutrophil populations in the lung following inflammatory lung injury. Based on our provocative Supporting Data, we have formulated the overarching hypothesis that neutrophil subpopulations can be therapeutically targeted during key phases of inflammatory lung injury to minimize lung injury without compromising host defense or lung repair. We propose the following specific aims: In Aim 1, we will define the dynamics of neutrophil subpopulations in the bone marrow, blood and lung during the progression of injury using lung injury models and targeted genetic interventions to study the roles of neutrophils during distinct phases of lung injury and repair. In Aim 2, we will define the receptor clustering and signaling mechanisms for the chemokine receptors CXCR2 and CXCR4 in neutrophils. In Aim 3, we will assess the therapeutic efficacy of targeting neutrophil subpopulations during discrete phases of inflammatory lung injury.