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A3844 - IL-17C, a Novel Cytokine that Promotes Neutrophil Recruitment, Is Differentially Expressed in Healthy Smokers and COPD Patients
Author Block: K. C. Jamieson1, S. Traves1, C. Dumonceaux2, A. N. Michi1, R. Leigh2, D. Proud1; 1Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada, 2Department of Medicine, University of Calgary, Calgary, AB, Canada.
RATIONALE: Chronic Obstructive Pulmonary Disease (COPD) exacerbations are predominantly triggered by bacterial and viral respiratory infections. Human rhinovirus (HRV) is the dominant viral pathogen identified, and non-typeable Haemophilus influenzae (NTHI) and Pseudomonas aeruginosa (PAO) are among the most common bacterial species detected. COPD patients who have bacteria-virus co-infections have more severe exacerbations, and increased risk of hospital readmission. The airway epithelium defends against these pathogens with a variety of mechanisms including pro-inflammatory and anti-microbial cytokine release. IL-17C is a novel cytokine in the IL-17 family that, unlike IL-17A, is released by the airway epithelium. IL-17C is suggested to have a pro-inflammatory role in the airway, although its exact functions have been poorly characterized. Studies indicate that IL-17C is highly expressed in epithelial biopsies of COPD patients compared to control subjects and we aim to understand the cause and consequence of this response. To date, there are no data assessing how respiratory viral infections affect IL-17C.
We hypothesize that human bronchial epithelial cells (HBECs) initiate IL-17C production in response to respiratory bacteria-virus co-infections as a protective anti-microbial mechanism and that this response is altered in COPD patients.
METHODS: Primary HBECs isolated from normal human lungs or HBECs isolated from bronchial brushings of healthy non-smokers, smokers with normal lung function (healthy smokers), and patients with confirmed COPD, were treated with bacteria (NTHI or PAO) and/or HRV for up to 72 hours. HBECs were exposed to IL-17C to assess its functional role. Protein and mRNA levels were measured using ELISA and qRT-PCR, respectively. Neutrophils were isolated from the blood of healthy donors and chemotaxis was assessed using a Boyden chamber.
RESULTS: Bacteria/HRV co-exposure induced synergistic IL-17C release from HBECs through NF-κB signalling and RIG-I/MDA5 recognition of viral replication products. The microbial-induced IL-17C response is attenuated by cigarette smoke extract and in cells from healthy smokers. Interestingly, cells from COPD patients had an enhanced IL-17C response to bacteria-virus co-infections compared to healthy smokers and non-smokers. IL-17C induces epithelial cells to release GROα, and supernatants from IL-17C-stimulated HBECs recruit neutrophils.
CONCLUSION: Bacteria-virus co-infections result in a robust IL-17C response from the airway epithelium, which then acts in an autocrine/paracrine manner to promote neutrophil recruitment. Differential IL-17C responses between healthy smokers and COPD patients suggest that further studies are needed to determine if IL-17C is a predictive biomarker of COPD in smokers, or if the response is a consequence of the inflammatory environment.