• Elizabeth A Oczypok, Pavle S Milutinovic, John F Alcorn, Anupriya Khare, Lauren T Crum, Michelle L Manni, Michael W Epperly, Adriane M Pawluk, Anuradha Ray, and Tim D Oury.
• Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
• J. Allergy Clin. Immunol. 2015 Sep 1;136(3):747-756.e4.

BackgroundSingle nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33.ObjectiveWe sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung.MethodsAAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses.ResultsRAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract.ConclusionsFor the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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