Understanding the impact of group 2 innate lymphoid cells on airway epithelial regeneration and repair

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ABSTRACT Epithelial dysfunction is critical in the pathogenesis of human conducting airway diseases such as COPD and asthma. Immune cells are known to influence epithelial composition and function in a variety of tissues. Group 2 innate lymphoid cells (ILC2s) are immune cells that have recently been shown to promote epithelial repair in the lung parenchyma in several murine injury models by promoting growth of distal facultative epithelial progenitors. While hyperactive ILC2s in the airway are known to contribute to chronic airway inflammation, the role of ILC2s in regulating epithelial regeneration and repair in the airway is unknown. To address this gap in knowledge, we will study ILC2s in the context of epithelial injury in the mouse trachea, which models the biology of the human conducting airways. Normal epithelial repair in the trachea occurs via expansion and differentiation of basal stem cells that give rise to all airway epithelial lineages. We will test the hypothesis that ILC2s contribute to airway epithelial repair by regulating proliferation and differentiation of basal cells. We hypothesize that the epithelial alarmin interleukin-33 (IL-33) is a critical signaling factor that initiates immune cell activation during airway regeneration and repair. Aim 1 will characterize the ILC2 response to airway injury and determine whether ILC2s are required for effective epithelial repair. Aim 2 will examine the IL-33/ST2 signaling axis as a potential mechanism by which immune cells respond to injury and promote repair. Targeted transgenic deletion and manipulation of ILC2s will provide cell-specific evidence of ILC2 involvement in airway epithelial regeneration. Interrogation of intracellular phosphorylation events and cytokine production will further elucidate the signaling mechanisms that promote epithelial remodeling and regeneration. Understanding the mechanisms of ILC2 activation and regulation of airway epithelial function will contribute to our understanding of human airway biology and provide potential targets for the therapeutic immunomodulation of human airway diseases.