IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation

Abstract

Background Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared to OVA or RSV mice alone. Further, IL-17A was only increased in OVA/RSV mice. Objective To determine if IL-17A increases AR and inflammation in the OVA/RSV model. Methods Wild-type BALB/c and IL-17A KO mice underwent mock, RSV, OVA, or OVA/RSV protocols. Lungs, bronchoalveolar lavage (BAL) fluid, and/or mediastinal lymph nodes (MLNs) were harvested post infection. Cytokine expression was determined by flow cytometry and ELISA in the lungs or BAL fluid. MLNs were restimulated with either OVA (323–229) peptide or RSV M2 (127–135) peptide and IL-17A protein expression was analyzed. AR was determined by methacholine challenge. Results RSV increased IL-17A protein expression by OVA-specific T cells 6 days post infection. OVA/RSV mice had decreased IFN-α and IFN-β protein expression compared to RSV mice. OVA/RSV mice had increased IL-23 mRNA expression in lung homogenates compared to mock, OVA, or RSV mice. Unexpectedly, IL-17A KO OVA/RSV mice had increased AR compared to WT OVA/RSV mice. Further, IL-17A KO OVA/RSV mice had increased eosinophils, lymphocytes, and IL-13 protein expression in BAL fluid compared to WT OVA/RSV mice. Conclusions IL-17A negatively regulated AR and airway inflammation in OVA/RSV mice. This finding is important because IL-17A has been identified as a potential therapeutic target in asthma, and inhibiting IL-17A in the setting of virally induced asthma exacerbations may have adverse consequences.

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

“…These cytokines have been shown to be involved in the various aspects of pathogenesis of respiratory diseases and in human natural and experimental RSV infections by regulating lung inflammation, mucus production, oxidative response, airway neutrophilia, AHR, T cell responses, and viral replication (25,(37)(38)(39)(40)(41).…”

IL-17 in lung disease: friend or foe?

“…IL-17-producing γδT cells have been shown to mediate the resolution of allergic airway inflammation and airway hyperreactivity in a murine model of ovalbumin-induced allergic inflammation while adoptive transfer of Th17 cells had no such effect 4. In Thorax , IL-17 has been shown to inhibit respiratory syncytial virus induced airway hyperresponsiveness during ovalbumin-induced allergic inflammation 5. These data suggest that IL-17 may play different roles in the airway, depending on the cellular source and context.…”

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

“…If IL-17 stabilizes IL-8 and IL-6, especially in the context of inflammation, the abnormal production of IL-17 in the acute response to P. aeruginosa may initiate the dysregulated inflammatory response in CF by inducing a consistent source of chemokines which are involved in neutrophil recruitment, exaggerating an already augmented inflammatory response in CF. Therefore, inhibition of IL-17 function during acute pulmonary exacerbations might be an alternative route to decreasing the neutrophil chemokine production and subsequent neutrophil influx that occurs during exacerbations (47).…”

“…While IL-17 has a role in the normal host immune response to Gram-negative bacterial infections (8,44), it has been associated with a wide spectrum of diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease, in which there is a dysregulated inflammatory response typically in the absence of a coexisting bacterial infection (17,(45)(46)(47)(48). Further, the IL-17 receptor appears to be ubiquitously expressed throughout the body, implicating IL-17 as an important regulator of the host response during chronic inflammation (49,50).…”