Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:136

Article

Oczypok, Elizabeth A.¹  Milutinovic, Pavle S.¹  Alcorn, John F.³  Khare, Anupriya²  Crum, Lauren T.¹  Manni, Michelle L.³  Epperly, Michael W.⁴  Pawluk, Adriane M.¹  Ray, Anuradha²  Oury, Tim D.¹ 

[1] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

[2] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA

[3] Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA

[4] Univ Pittsburgh, Dept Radiat Oncol, Inst Canc, Pittsburgh, PA USA

关键词: Asthma;    receptor for advanced glycation end-products;    IL-33;    group 2 innate lymphoid cells;   

DOI  :  10.1016/j.jaci.2015.03.011

来源: Elsevier

【 摘 要 】

Background: Single 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. Objective: We sought to test the hypothesis that pulmonaryRAGE is necessary for allergen-induced ILC2 accumulation in the lung. Methods: AAI 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. Results: RAGE 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. Conclusions: For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.

【 授权许可】

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