IL-17-producing-ST2+ILC2 plays a pathogenic role in lung inflammation

Publication date: Available online 3 April 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Ting Cai, Jinxin Qiu, Yan Ji, Wenjing Li, Zhaoyun Ding, Caixia Suo, Jiali Chang, Jingjing Wang, Rui He, Youcun Qian, Xiaohuan Guo, Liang Zhou, Huiming Sheng, Lei Shen, Ju Qiu
BackgroundIL-17 plays a pathogenic role in asthma. ST2⁻iILC2s (inflammatory group 2 innate lymphoid cells) driven by IL-25 can produce IL-17, while ST2⁺nILC2s (natural ILC2s) produce few IL-17.ObjectiveWe characterized the ST2⁺IL-17⁺ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2⁺IL-17⁺ILC2s.MethodsLung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1^−/−, Rorc^gfp/gfp and Ahr^−/− mice was examined by flow cytometry. Bone marrow transfer experiment was performed to evaluate hematopoietic MyD88 signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naïve ILC2s treated with IL-33, leukotrienes and inhibitors for NFAT, p38, JNK or NF-κB. The pathogenesis of IL-17⁺ILC2s was determined by transferring wild-type or Il17^−/−ILC2s to Rag2^−/−Il2rg^−/− mice which were further induced lung inflammation. Finally, the expression of 106 ILC2 signature genes was compared between ST2⁺IL-17⁺ILC2s and ST2⁺IL-17⁻ILC2s.ResultsPapain or IL-33 treatment boosted IL-17 production from ST2⁺ILC2s (we name them as ILC217), but not ST2⁻ILC2s. Ahr, but not RORγt, facilitated the production of IL-17 by ILC217s. Hematopoietic compartment of MyD88 signaling is essential for the induction of ILC217s. IL-33 works in synergy with leukotrienes, which signal through NFAT activation, to promote IL-17 in ILC217s. Il17^−/− ILC2s were less pathogenic in lung inflammation. ILC217s concomitantly expressed IL-5 and IL-13 but expressed few GM-CSF.ConclusionDuring lung inflammation, IL-33 and leukotrienes synergistically induce ILC217s. ILC217s are highly pathogenic and unexpected source for IL-17 in lung inflammation.

Teaser

During lung inflammation, IL-33 and leukotrienes synergistically boost endogenous production of IL-17 from tissue-resident ST2⁺ILC2s. IL-17-producing ST2⁺ILC2s are highly pathogenic by recruiting leukocytes to airways and may be involved in severe forms of asthma.


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