IL-17–producing ST2+ group 2 innate lymphoid cells play a pathogenic role in lung inflammation - 04/01/19
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−/−, Rorcgfp/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.
Le texte complet de cet article est disponible en PDF.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
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.). |
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 1
P. 229 - janvier 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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