RAGE-dependent VCAM-1 expression in the lung endothelium mediates IL-33 induced allergic airway inflammation.

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 been previously shown that RAGE acts both upstream of interleukin-33 (IL-33) release and downstream of IL-33 release via RAGE-dependent 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 mediates downstream IL-33 induced type 2 inflammatory responses is unknown.

OBJECTIVE: This study tests the hypothesis that ILC2s are recruited to the lungs via RAGE-dependent vascular cell adhesion molecule 1 (VCAM-1) expression on lung endothelial cells.

METHODS: House dust mite extract, Alternaria alternata extract or rIL-33 were used to induce AAI/VCAM-1 expression in wild-type (WT) and RAGE-knockout (RAGE-KO) mice. Intravenous (i.v.) anti-VCAM1 or intraperitoneal (i.p.) β7 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 VCAM-1 expression in WT, but not RAGE-KO cells. Administration of VCAM-1 and β7 integrin blocking antibodies reduced IL-33 induced eosinophilic inflammation, mucus metaplasia, and type 2 inflammatory responses CONCLUSION: This study demonstrates that allergen and cytokine-induced VCAM-1 expression is RAGE dependent, and contributes to lung ILC2 accumulation and downstream eosinophilic inflammation, mucus metaplasia, and type 2 inflammatory responses. This article is protected by copyright. All rights reserved.