Anaphylatoxin regulation of the IL-33-ILC2 axis



 DESCRIPTION (provided by applicant): Worldwide, the prevalence of allergic airway diseases (asthma, rhinitis, sinusitis, etc.) has been continuously rising in the past decades. Despite these statistics, much remains unknown about the processes that drive the aberrant Th2 immune responses at the root of allergic pathologies. A greater understanding of the mechanisms responsible for driving these aberrant Th2 immune responses would provide us with novel pathways for the development of new treatment approaches. Recent evidence suggests that the cytokine IL-33, and its receptor, ST2, have profound effects on regulating aberrant Th2 responses, and are significantly dysregulated in allergic disease, yet little is known about their regulation. Innate immune mediators have been shown to be central in regulating Th2 responses, and our previous work has demonstrated a central role for the complement pathway in regulating aberrant type 2 responses in the lungs. Using mouse models of Th2 allergic airway inflammation, we provide evidence that the anaphylatoxins (C3a and C5a) regulate the allergic response to allergen, and have direct actions on regulating IL-33 production. The IL-33-ST2 pathway has been shown to drive type 2 responses through its central role in the development of a newly described lymphoid cell type (innate lymphoid cells-ILC). Our preliminary data suggests that complement regulates aberrant type 2 responses through multiple non-mutually exclusive pathways: by directly regulating IL-33 production from the lung epithelium and by directly engaging ILCs to control their production of IL-13 and their role as antigen-presenting cells (APCs). Three specific aims are proposed to advance our understanding of the regulation of the IL-33-ILC2 axis by anaphylatoxins. Specific Aim 1 will further our understanding of anaphylatoxin regulation of allergen- induced IL-33. Specific Aim 2 will determine the role of anaphylatoxin signaling on ILCs in regulating IL-13 production. Specific Aim 3 will directly test the role of anaphylatoxin signaling in modulating the APC activity of ILCs Collectively, the studies proposed in this application will move us beyond our current understanding of how type innate 2 responses develop. Our studies will begin to characterize the central role of the complement pathway in balancing the outcome of innate type 2 responses in the lungs. A better understanding of these novel pathways will enable us to identify new targets for therapeutic interventions in individuals with dysregulated lung type 2 responses that are underserved by current therapies.