Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

Abstract

The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Th17 cytokine IL-17A is also implicated in asthma and has been shown to both positively and negatively regulate Th2-dependent responses in murine models of allergic airways disease. Our objective in this study was to better understand the role of IL-17 in airway inflammation by examining how IL-17 modifies IL-13–induced airway inflammatory responses. We treated BALB/c mice intranasally with IL-13 or IL-17 alone or in combination for 8 consecutive days, after which airway hyperresponsiveness, inflammatory cell influx into the lung, and lung chemokine/cytokine expression were assessed. As expected, IL-13 increased airway inflammation and airway hyperresponsiveness. IL-13 also increased numbers of IL-17–producing CD4+ and γδ T cells. Treating mice with a combination of IL-13 and IL-17 reduced infiltration of IL-17+ γδ T cells, but increased the number of infiltrating eosinophils. In contrast, coadministration of IL-13 with a higher dose of IL-17 decreased all IL-13–induced inflammatory responses, including infiltration of both IL-17+CD4+ and γδ T cells. To examine the inhibitory activity of IL-17–expressing γδ T cells in this model, these cells were adoptively transferred into naive recipients. Consistent with an inhibitory role for γδ T cells, IL-13–induced infiltration of eosinophils, lymphocytes, and IL-17+CD4+ T cells was diminished in recipients of the γδ T cells. Collectively, our data indicate that allergic airway inflammatory responses induced by IL-13 are modulated by both the quantity and the cellular source of IL-17.

IL-17 and neutrophils: unexpected players in the type 2 immune response

“…The expression of CD209a is highly upregulated in response to IL-4 or IL-13 [38,59,60], suggesting the potential for a amplification of IL-17 responses by type 2 cytokines. This is consistent with data in which instillation of IL-13 induces IL-17 producing CD4+ and gd T cells [61 ]. These observations that type 2 cytokines promote IL-17 production contrasts sharply with the previously described ability of type 2 cytokines to negatively regulate the IL-17 response [26 ,55 ,56] but this may reflect an important negative feedback loop.…”

“…innate lymphoid cells including gd cells vs adaptive Th17/Th2) [61 ]. Nonetheless, a general story in which early neutrophil-IL-17 activation initiates events that promote a subsequent type 2 response, which in turn suppresses excessive neutrophilia is likely to be common.…”

Adjuvant-dependent regulation of interleukin-17 expressing γδ T cells and inhibition of Th2 responses in allergic airways disease

“…Several cell types, including Th17 cells [24,31], γδ T cells [27,28] and alveolar macrophages [32] have been identified as sources of IL-17 in murine models of allergic airways disease. Following OVA challenge, we identified the major IL-17 producing cell(s) in both the BAL and lungs of OVA/sal, OVA/alum and OVA/CFA sensitized mice.…”

“…We therefore considered other mediators to provide a possible explanation for the disconnect between AHR and inflammation observed in OVA/CFA mice. The ability of IL-17 to act as both a positive and negative regulator of asthma [27], as well as the ability of CFA to induce IL-17 in models of experimental autoimmune encephalomyelitis [45] made this particular cytokine a strong candidate. While IL-17 alone may not induce AHR in mice, under some circumstances it can promote Th2-dependent AHR and inflammation [26].…”

“…A growing body of evidence suggests that IL-17, when sourced from Th17 cells, enhances Th2-induced eosinophilic inflammation and AHR [24,26], whereas we and others have shown that IL-17-γδ T cells negatively regulate these responses [27,28]. We have now compared how two widely used adjuvants, alum and CFA, modulate OVA-induced allergic airways disease.…”