Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2

Abstract

AbstractExposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely T helper cell type 2 (Th2) dominant and a number of innate immune receptors have been identified which recognize HDM to initiate a Th2 response. Nucleotide-binding Oligomerization Domain-containing Protein 2 (NOD2) is a cytosolic sensor of peptidoglycan which is important for Th2 polarization. NOD2 mediates its signaling through its downstream effector kinase, Receptor-interacting Serine/Threonine Protein Kinase 2 (RIP2). We have previously shown that RIP2 is important in promoting HDM-associated allergic airway inflammation and Th2 immunity. In particular, we demonstrated that the effects of RIP2 were important early in the HDM response, likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while skewing the immune response from Th2 towards Th1. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2 targeted therapies.