Divergent Roles for Airway Epithelial MMP7 and Retinoic Acid in Experimental Asthma

The innate immune response of airway epithelial cells to aeroallergen initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25 we show that epithelial matrix metalloproteinase 7 (MMP7) was expressed in asthma and was required for maximal activity of IL-25 in promoting T helper type 2 cell differentiation. Allergen-challenged Mmp7(−/−) mice showed reduced airway hyperreactivity, allergic inflammatory cytokine production and increased expression of retinal dehydrogenase (RALDH)-1. Inhibition of RALDH-1 restored the asthma phenotype in Mmp7(−/−) mice and inhibited lung T regulatory cell responses while exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating IL-25 while simultaneously inhibiting retinoid-dependent T regulatory cell development.