| First Author | Cai T | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 143 |
| Issue | 1 | Pages | 229-244.e9 |
| PubMed ID | 29625134 | Mgi Jnum | J:313223 |
| Mgi Id | MGI:6791681 | Doi | 10.1016/j.jaci.2018.03.007 |
| Citation | Cai T, et al. (2019) IL-17-producing ST2(+) group 2 innate lymphoid cells play a pathogenic role in lung inflammation. J Allergy Clin Immunol 143(1):229-244.e9 |
| abstractText | 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 kappa 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 gammat, 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. |
