Haemophilus influenzae Infection Drives IL-17-Mediated Neutrophilic Allergic Airways Disease

Abstract

A subset of patients with stable asthma has prominent neutrophilic and reduced eosinophilic inflammation, which is associated with attenuated airways hyper-responsiveness (AHR). Haemophilus influenzae has been isolated from the airways of neutrophilic asthmatics; however, the nature of the association between infection and the development of neutrophilic asthma is not understood. Our aim was to investigate the effects of H. influenzae respiratory infection on the development of hallmark features of asthma in a mouse model of allergic airways disease (AAD). BALB/c mice were intraperitoneally sensitized to ovalbumin (OVA) and intranasally challenged with OVA 12–15 days later to induce AAD. Mice were infected with non-typeable H. influenzae during or 10 days after sensitization, and the effects of infection on the development of key features of AAD were assessed on day 16. T-helper 17 cells were enumerated by fluorescent-activated cell sorting and depleted with anti-IL-17 neutralizing antibody. We show that infection in AAD significantly reduced eosinophilic inflammation, OVA-induced IL-5, IL-13 and IFN-γ responses and AHR; however, infection increased airway neutrophil influx in response to OVA challenge. Augmented neutrophilic inflammation correlated with increased IL-17 responses and IL-17 expressing macrophages and neutrophils (early, innate) and T lymphocytes (late, adaptive) in the lung. Significantly, depletion of IL-17 completely abrogated infection-induced neutrophilic inflammation during AAD. In conclusion, H. influenzae infection synergizes with AAD to induce Th17 immune responses that drive the development of neutrophilic and suppress eosinophilic inflammation during AAD. This results in a phenotype that is similar to neutrophilic asthma. Infection-induced neutrophilic inflammation in AAD is mediated by IL-17 responses.

Importance of Mast Cell Prss31/Transmembrane Tryptase/Tryptase-γ in Lung Function and Experimental Chronic Obstructive Pulmonary Disease and Colitis

“…In each instance, a single drop of blood was smeared onto a microscope glass slide, which was then stained with H&E. The differential cell populations were enumerated based on their morphology, as described previously (32).…”

Pneumococcal Components Induce Regulatory T Cells That Attenuate the Development of Allergic Airways Disease by Deviating and Suppressing the Immune Response to Allergen

“…Other studies have shown that blocking membrane-bound IL-6R, with anti-IL-6R Ab induces Tregs and attenuates AAD (38). Because the Th17 cell cytokines IL-25 and IL-17 contribute to the inflammatory milieu in AAD (13,39), and these factors were suppressed by treatment (Fig. 4J, 4K), T+P may be effective in suppressing Th17-mediated asthma pathogenesis.…”

“…Airway hyperresponsiveness AHR was assessed as described previously (13)(14)(15). Briefly, anesthetized and tracheotomized mice were cannulated and connected to inline aerosol and ventilator apparatus.…”

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

“…In addition, IL-17A was described to affect airway inflammation through several pathways. IL-17A induces indirect activation and infiltration of neutrophils into the airways, partially through induction of KC expression in structural cells of the airways (38,39). Furthermore, IL-17A seems also to be able to amplify Th2 immune responses (40,41).…”