IL-17–producing ST2⁺ group 2 innate lymphoid cells play a pathogenic role in lung inflammation - 06/08/18

Doi : 10.1016/j.jaci.2018.03.007

Ting Cai, BS ^a,^{∗
These authors contributed equally to this work.}, Jinxin Qiu, BS ^a,^{∗
These authors contributed equally to this work.}, Yan Ji, PhD ^a, Wenjing Li, MS ^b, Zhaoyun Ding, BS ^a, Caixia Suo, PhD ^a, Jiali Chang, BS ^a, Jingjing Wang, BS ^a, Rui He, MD, PhD ^b, Youcun Qian, PhD ^a, Xiaohuan Guo, PhD ^c,^d, Liang Zhou, MD, PhD ^e, Huiming Sheng, MD, PhD ^f,^⁎,^{‡
These authors contributed equally to this work.} , Lei Shen, PhD ^g,^⁎,^{‡
These authors contributed equally to this work.} , Ju Qiu, PhD ^a,^⁎,^{‡
These authors contributed equally to this work.}
^a CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
^b Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
^c Institute for Immunology, Tsinghua University, Beijing, China
^d Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
^e Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Fla
^f Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
^g Shanghai Institute of Immunology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China

^∗Corresponding author: Ju Qiu, PhD, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, New Lifesciences Building, Rm 1724, No. 320 Yueyang Road, Shanghai 20031, China.Shanghai Institutes for Biological SciencesChinese Academy of SciencesNew Lifesciences BuildingRm 1724, No. 320 Yueyang RoadShanghai20031China^∗Lei Shen, PhD, Shanghai Jiao Tong University School of Medicine, B5-1202, 280 South Chongqing Road, Shanghai 200025, China.Shanghai Jiao Tong University School of MedicineB5-1202, 280 South Chongqing RoadShanghai200025China^∗Huiming Sheng, MD, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.Tongren HospitalShanghai Jiao Tong University School of MedicineShanghai200336China

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Abstract

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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Key words : Asthma, group 2 innate lymphoid cells, IL-17

Abbreviations used : Ahr, BALF, CsA, GFP, iILC2, ILC2, JNK, LTC₄, LTD₄, MyD88, NFAT, NF-κB, nILC2, PAS, RORγt

Plan

Methods

Mice

Induction of lung inflammation using IL-33 and papain

Isolation of lung lymphocytes

Isolation of large intestinal lamina propria lymphocytes

Flow cytometry

In vitro ILC2 culture

In vivo treatment with CsA or FK506

Detection of LTC₄ and IL-17 by means of ELISA

Bone marrow transplantation

In vivo blockade of IL-17 or IL-25

Induction of lung inflammation in Rag2^−/−Il2rg^−/− mice

Analysis of BALF

Histologic analyses

Measurement of airway responsiveness to methacholine

Detection of mRNA by using real-time RT-PCR

Analyzing expression of ILC2 signature genes by using real-time RT-PCR

Statistical methods

Results

IL-33 induces IL-17–producing ILC2s independently of the adaptive immune system

Induction of IL-17–producing ST2⁺ ILC2s is independent of RORγt

Ahr facilitates IL-17 production by ILC2₁₇s

MyD88 signaling from the hematopoietic compartment is essential for ILC2₁₇ induction

Sustained IL-33 signal is essential for maintenance of ILC2₁₇s

Leukotrienes and IL-33 synergistically induce mRNA expression of IL-17 in ILC2s

ILC2₁₇s play a pathogenic role in IL-33–induced lung inflammation

ILC2₁₇s concomitantly express IL-5 and IL-13 but little GM-CSF

Discussion

Supported by grants 2015CB943400 and 2014CB943300 from the Ministry of Science and Technology of China, grant XDB19000000 from the Strategic priority Research Program of the Chinese Academy of Sciences, grants 91542102 and 31570887 from the National Natural Science Foundation of China and China's Youth 1000-Talent Program (to J.Q.) and grant 16ZR1449900 from the Natural Science Foundation of Shanghai and grant 2017323 from the Youth Innovation Promotion Association of the Chinese Academy of Sciences (to Y.J.). The work was also supported by the National Institutes of Health (DK105562 and R01AI132391 to L.Z.), and by a Cancer Research Institute Investigator Award (to L.Z.). L.Z. is a Pew Scholar in Biomedical Sciences supported by the Pew Charitable Trusts and an Investigator in the Pathogenesis of Infectious Disease supported by the Burroughs Wellcome Fund. The work was also supported by National Natural Science Foundation of China grant 81571533 (to L.S.) and China's Youth 1000-Talent Program (to L.S.).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.