Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity
Department of Medicine, Division of Infectious Diseases and Immunology
Analysis of Variance; Animals; Asthma; Carrier Proteins; Cell Proliferation; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Homeodomain Proteins; Inflammasomes; Interleukin-17; Interleukin-1beta; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Reverse Transcriptase Polymerase Chain Reaction
Cells | Circulatory and Respiratory Physiology | Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease | Respiratory System
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-1beta. Macrophage-derived IL-1beta production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1beta 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-1beta and ILC3 cells.
DOI of Published Version
Nat Med. 2014 Jan;20(1):54-61. doi: 10.1038/nm.3423. Epub 2013 Dec 15. Link to article on publisher's site
Kim, Hye Young; Lee, Hyun Jun; Chang, Ya-Jen; Pichavant, Muriel; Shore, Stephanie A.; Fitzgerald, Katherine A.; Iwakura, Yoichiro; Israel, Elliot; Bolger, Kenneth; Faul, John; DeKruyff, Rosemarie H.; and Umetsu, Dale T., "Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity" (2014). Infectious Diseases and Immunology Publications and Presentations. 188.