The Role of IL-25 in Innate Cytokine Production and Pulmonary Immunopathology.

Abstract

The mucosal surfaces of the lung and intestinal tract are areas at which heterogeneous immune populations must function in concert to maintain barrier integrity and coordinate appropriate responses to both pathogenic and innocuous antigens. The Interleukin-17 (IL-17) family member IL-25 is a cytokine associated with allergy and asthma which functions to promote type 2 and suppress alternative inflammatory responses in epithelial tissues. This study identifies the IL-25 receptor, IL-17RB, as an important mediator of both innate and adaptive type 2 immune responses in the context of allergic airways disease and respiratory viral infection. Through a series of animal models, genetic manipulations, adoptive transfers, and a comprehensive characterization of IL-25 responsive myeloid populations, we have identified a novel granulocytic population of innate IL-25 responsive cells involved in the pathogenesis of allergic asthma. This population, termed Type 2 Myeloid (T2M) cells, produces the type 2 cytokines IL-4 and IL-13, is recruited in large numbers to the lung in response to IL-25 secretion, and induces IL-25 associated immunopathology in the airway. Our findings also indicate that T2M cells may be of significant clinical importance. High dose dexamethasone administration, the front line therapy for severe allergic asthma exacerbations, did not reduce cytokine production in, or total numbers of, T2M cells. Finally, a clinical study using peripheral blood drawn from atopic asthmatic volunteers identified a similar IL-4 and IL-13 producing granulocytic population that was not observed in non-atopic volunteers. The identification of a novel, pathologically relevant granulocytic subset offers an important new avenue for research investigation with the potential for significant translational impact.