Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma

Abstract

Interleukin (IL)-17 is produced by activated memory CD4(+) cells and induces cytokines and chemokines that stimulate neutrophil generation and recruitment. Here, we investigated the involvement of IL-17 in the bronchial influx of neutrophils in experimental allergic asthma. Inhalation of nebulized ovalbumin (OVA) by sensitized mice with bronchial eosinophilic inflammation resulting from chronic OVA exposure induced early IL-17 mRNA expression in inflamed lung tissue, concomitant with a prominent bronchial neutrophilic influx. Anti-IL-17 monoclonal antibodies (mAb) injected before allergen inhalation strongly reduced bronchial neutrophilic influx, in a manner equally as potent as the anti-inflammatory dexamethasone. Remarkably, anti-IL-17 mAb significantly enhanced IL-5 levels in both BAL fluid and serum, and aggravated allergen-induced bronchial eosinophilia. In another series of experiments, anti-IL-17 mAb were given repeatedly during the inhalatory challenge phase with OVA of sensitized mice. This treatment regimen abated bronchial neutrophilia in parallel with reduction of bone marrow and blood neutrophilia. In addition, anti-IL-17 mAb treatment elevated eosinophil counts in the bone marrow and bronchial IL-5 production, without alteration of allergen-induced bronchial hyperresponsiveness. In summary, our results demonstrate that IL-17 expression in airways is upregulated upon allergen inhalation, and constitutes the link between allergen-induced T cell activation and neutrophilic influx. Because neutrophils may be important in airway remodeling in chronic severe asthma, targeting IL-17 may hold therapeutic potential in human asthma.

IL-23 Compensates for the Absence of IL-12p70 and Is Essential for the IL-17 Response during Tuberculosis but Is Dispensable for Protection and Antigen-Specific IFN-γ Responses if IL-12p70 Is Available

“…We show in this study that in the absence of IL-17, the development of the mycobacterial mononuclear granuloma is not substantially altered. This failure is particularly surprising in view of the reported role of IL-17 as a mediator of inflammation in asthma (41), pneumonia (12), airway hypersensitivity (16), and neutrophil recruitment to the lung (30 -32). It is also surprising because inflammatory responses are compromised in the absence of IL12p40 (7), IL-23 (14), and IL-17 (16), but not in the absence of IFN-␥ (42) or IL-12p35 (7,14).…”

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma

“…[32][33][34][35][36] IL-17A also plays a role in human asthmatic patients and in airways of allergic animals. 18,28,30,[37][38][39] Studies have found that in patients with moderate-to-severe asthma, neutrophils are found to be more abundant than eosinophils in the bronchoalveolar lavage fluid. 30,31,40 IL-17A can promote neutrophil recruitment, which might contribute to certain asthmatic phenotypes characterized by both high neutrophil counts and IL-17A expression.…”

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

“…Increased levels of IL-17 were reported to correlate with disease intensity in allergic lung inflammation as observed in OVA-sensitized mice [12], in peritoneal inflammation after infection with Bacteroides fragilis [13], in rheumatoid arthritis [14], in multiple sclerosis [15] and in psoriasis [16].…”