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 HY, Lee HJ, Chang Y, Pichavant M, Shore SA, Fitzgerald KA, Iwakura Y, Israel E, Bolger K, Faul J, DeKruyff RH, Umetsu DT. (2014). Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Infectious Diseases and Immunology Publications. https://doi.org/10.1038/nm.3423. Retrieved from https://escholarship.umassmed.edu/infdis_pp/188