Dataset Information

Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity.

ABSTRACT: Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a(-/-) or Nlrp3(-/-) mice. AHR was also associated with the expansion of CCR6(+) type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2(-/-); Il2rg(-/-) mice treated with recombinant IL-1?. Macrophage-derived IL-1? production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1? with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1? and ILC3 cells.

SUBMITTER: Kim HY

PROVIDER: S-EPMC3912313 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity.

Kim Hye Young HY Lee Hyun Jun HJ Chang Ya-Jen YJ Pichavant Muriel M Shore Stephanie A SA Fitzgerald Katherine A KA Iwakura Yoichiro Y Israel Elliot E Bolger Kenneth K Faul John J DeKruyff Rosemarie H RH Umetsu Dale T DT

Nature medicine 20131215 1

Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 infl ...[more]

PMID: 24336249

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Project description: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 ? 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 ?t, 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.

Dataset Information

Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity.

Publications

Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity.

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