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 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 ILC2 17 s) but not ST2 − ILC2s. Ahr, but not retinoic acid receptor–related orphan receptor γt, 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.