IL-17A Promotes the Exacerbation of IL-33–Induced Airway Hyperresponsiveness by Enhancing Neutrophilic Inflammation via CXCR2 Signaling in Mice

Abstract

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.

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

“…Per a 10 acts via PAR-2 receptors [8], which explains the relatively higher levels of IL-17A in the BALF of Per a 10 immunized mice. This, along with the influx of neutrophils in lungs of Per a 10 immunized mice is in accordance with previous studies where IL-17A is shown to increase neutrophilic infiltration [25].…”

“…Per a 10 acts via PAR-2 receptors [8], which explains the relatively higher levels of IL-17A in the BALF of Per a 10 immunized mice. This, along with the influx of neutrophils in lungs of Per a 10 immunized mice is in accordance with previous studies where IL-17A is shown to increase neutrophilic infiltration [25].Costimulatory molecules on antigen presenting cells along with the cytokine milieu play a critical role in determining the type of T-cell response. OX40L is an important costimulatory molecule expressed on a wide variety of cells including APCs.…”

Interleukin (IL)-33: New Therapeutic Target for Atopic Diseases

“…Steroid resistance may be attributed to activation of the STAT5 signaling pathway by TSLP, which cannot be suppressed by corticosteroids in NH cells (26). Similar to this finding, airway inflammation induced by a combined treatment with IL-33 and IL-17 was also found to be resistant to dexamethasone (19).…”

“…These two phenomena may be related to each other. IL-33-mediated airway inflammation augmented by the neutrophil-related cytokine, IL-17, could not be suppressed by dexamethasone (19).…”

Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α

“…4C). IL-17A has the capacity to induce both AHR and neutrophil recruitment (28,29,38). We and others have reported that IL-17 contributes to the AHR caused by repeated O 3 exposure in lean mice (43,44).…”