IL-17–producing ST2+ group 2 innate lymphoid cells play a pathogenic role in lung inflammation

Publication date: January 2019

Source: Journal of Allergy and Clinical Immunology, Volume 143, Issue 1

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

Background

IL-17 plays a pathogenic role in asthma. ST2⁻ inflammatory group 2 innate lymphoid cells (ILC2s) driven by IL-25 can produce IL-17, whereas ST2⁺ natural ILC2s produce little IL-17.

Objective

We characterized ST2⁺IL-17⁺ ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2⁺IL-17⁺ ILC2s.

Methods

Lung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1^−/−, Rorc^gfp/gfp, and aryl hydrocarbon receptor (Ahr)^−/− mice was examined by using flow cytometry. Bone marrow transfer experiments were performed to evaluate hematopoietic myeloid differentiation primary response gene–88 (MyD88) signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naive ILC2s treated with IL-33, leukotrienes, and inhibitors for nuclear factor of activated T cells, p38, c-Jun N-terminal kinase, or nuclear factor κ light-chain enhancer of activated B cells. The pathogenesis of IL-17⁺ ILC2s was determined by transferring wild-type or Il17^−/− ILC2s to Rag2^−/−Il2rg^−/− mice, which further induced lung inflammation. Finally, expression of 106 ILC2 signature genes was compared between ST2⁺IL-17⁺ ILC2s and ST2⁺IL-17⁻ ILC2s.

Results

Papain or IL-33 treatment boosted IL-17 production from ST2⁺ ILC2s (referred to by us as ILC2₁₇s) but not ST2⁻ ILC2s. Ahr, but not retinoic acid receptor–related orphan receptor γt, facilitated the production of IL-17 by ILC2₁₇s. The hematopoietic compartment of MyD88 signaling is essential for ILC2₁₇ induction. IL-33 works in synergy with leukotrienes, which signal through nuclear factor of activated T-cell 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 little GM-CSF.

Conclusion

During lung inflammation, IL-33 and leukotrienes synergistically induce ILC2₁₇s. ILC2₁₇s are a highly pathogenic and unexpected source for IL-17 in lung inflammation.

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