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

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 ILC2(17)s) but not ST2(-) ILC2s. Ahr, but not retinoic acid receptor-related orphan receptor gamma t, facilitated the production of IL-17 by ILC2(17)s. The hematopoietic compartment of MyD88 signaling is essential for ILC2(17) induction. IL-33 works in synergy with leukotrienes, which signal through nuclear factor of activated T-cell activation to promote IL-17 in ILC2(17)s. Il17(-/-) ILC2s were less pathogenic in lung inflammation. ILC2(17)s concomitantly expressed IL-5 and IL-13 but expressed little GM-CSF. Conclusion: During lung inflammation, IL-33 and leukotrienes synergistically induce ILC2(17)s. ILC2(17)s are a highly pathogenic and unexpected source for IL-17 in lung inflammation.