IL-17A promotes the exacerbation of IL-33-induced airway hyperresponsiveness by enhancing neutrophilic inflammation via CXCR2 signaling in mice.
Neutrophilic airway inflammation is a hallmark of patients with severe asthma. Although we have reported that both IL-33 and IL-17A contributed to IgE-mediated neutrophilic inflammation in mice, the relationship remains unclear. In this article, we examined how IL-17A modifies IL-33-induced neutrophilic inflammation and airway hyperresponsiveness (AHR). IL-33 was intratracheally administered to BALB/c mice on days 0-2; furthermore, on day 7, the effect of the combination of IL-33 and IL-17A was evaluated. Compared with IL-33 or IL-17A alone, the combination exacerbated neutrophilic inflammation and AHR, associated with more increased levels of lung glutamic acid-leucine-arginine(+) CXC chemokines, including CXCL1, CXCL2, and CXCL5, and infiltration by alveolar macrophages expressing CXCR2. Treatment with anti-CXCR2 mAb or depletion of alveolar macrophages repressed neutrophilic inflammation and AHR; in addition, depletion of neutrophils suppressed AHR. These findings prompted us to examine the role of CXCR2 in IgE-sensitized mice; a single treatment with anti-CXCR2 mAb in the seventh Ag challenge inhibited late-phase airway obstruction, AHR, and neutrophilic inflammation. In addition to inhibition, multiple treatments during the fourth to seventh challenge attenuated early-phase airway obstruction, eosinophilic inflammation, and goblet cell hyperplasia associated with the reduction of Th2 cytokine production, including IL-4, IL-5, and IL-13. Collectively, IL-33 cooperated with IL-17A to exacerbate AHR by enhancing neutrophilic inflammation via CXCR2 signaling; furthermore, CXCR2 signaling derived Th2 responses. We thus suggest the underlying mechanisms of IL-33 and IL-17A in allergic asthma and CXCR2 as potential therapeutic targets for the disease.
Department of Pharmacology, Kobe Pharmaceutical University, Higashinada, Kobe 658-8558, Japan.
Nobuaki
N
Mizutani
Takeshi
T
Nabe
Shin
S
Yoshino
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D054365:Chemokine CXCL5 / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology; D020397:Goblet Cells / Q000276:immunology; D007073:Immunoglobulin E; D007249:Inflammation / Q000276:immunology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008168:Lung / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C094739:Cxcl5 protein, mouse; C098680:Il17a protein, mouse; C506535:Il33 protein, mouse; D018793:Interleukin-13; D020381:Interleukin-17; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D023063:Receptors, Interleukin-8B; D015847:Interleukin-4; D007073:Immunoglobulin E