title: 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-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β 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-1β and ILC3 cells.
authors: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Hye Young
authors: HY
authors: Kim
authors: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Hyun Jun
authors: HJ
authors: Lee
authors: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Ya-Jen
authors: YJ
authors: Chang
authors: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Muriel
authors: M
authors: Pichavant
authors: Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Stephanie A
authors: SA
authors: Shore
authors: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts, Worcester, Massachusetts, USA.
authors: Katherine A
authors: KA
authors: Fitzgerald
authors: Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Elliot
authors: E
authors: Israel
authors: Respiratory Department, Connolly Hospital Blanchardstown, Dublin, Ireland.
authors: Kenneth
authors: K
authors: Bolger
authors: Respiratory Department, Connolly Hospital Blanchardstown, Dublin, Ireland.
authors: John
authors: J
authors: Faul
authors: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Rosemarie H
authors: RH
authors: DeKruyff
authors: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Dale T
authors: DT
authors: Umetsu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D049109:Cell Proliferation; D059305:Diet, High-Fat; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics; D058847:Inflammasomes / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000150:complications*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D018398:Homeodomain Proteins; D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C064658:RAG-1 protein