Rage-Dependent Vcam-1 Expression In The Pulmonary Endothelium Mediates Il-33 Induced Asthma Pathogenesis

Background: The receptor for advanced glycation endproducts (RAGE) has been implicated as a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation (AAI). It has previously been shown that RAGE acts both upstream and downstream of interleukin-33 (IL-33) release and via IL-33 induced accumulation of type 2 innate lymphoid cells (ILC2s) in the lungs, which perpetuate type 2 inflammation and mucus metaplasia. However, the mechanism by which RAGE promotes ILC2 accumulation in the lung in response to allergens or rIL-33 remains unknown. Objective: this study tests the hypothesis that ILC2s are recruited to the lungs via RAGE-dependent VCAM1 expression in the pulmonary endothelium. Methods: House dust mite extract, Alternaria alternata extract or rIL-33 were used to induce AAI/VCAM1 expression in WT and RAGE-KO mice. Intravenous anti-VCAM1 blocking antibody administration was used to determine the role of VCAM-1 in IL-33 induced AAI. Results: Enhanced VCAM-1 expression in the lungs by HDM, AA, or rIL-33 exposure was found to be RAGE dependent. In addition, stimulation of primary mouse lung endothelial cells with IL-33 induced VCAM1 expression in WT but not RAGE-KO cells. Administration of VCAM1 blocking antibody prevented IL-33-induced airway eosinophilia, peribronchiolar eosinophilic inflammation, as well as mucus metaplasia. Blocking VCAM1 also diminished ILC2-derived type 2 cytokine production. Conclusion: This study demonstrates that RAGE mediates pulmonary ILC2 accumulation, eosinophilic inflammation and mucus metaplasia, by promoting VCAM-1 expression on pulmonary endothelial cells.