Quinolinic Acid modulates pulmonary inflammatory response to influenza infection

Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction and chronic inflammation mainly due to exposure to harmful particles, such as smoking. Patients with COPD frequently develop exacerbations, mostly caused by infections, often viral, leading to death. The tryptophan catabolic pathway, leading to NAD production, is also affected by cigarette smoke (CS) which causes modifications of its metabolites. Quinolinic acid (QA), an active metabolite with immunomodulatory properties is affected in COPD patients; our aim was to determine the potential role of tryptophan pathway and specifically of QA, in the control of COPD exacerbations. We analyzed the kynurenine pathway in Human bronchial epithelial cells (BEAS-2B) infected with influenza H3N2 and exposed or not to CS extract (CSE). BEAS-2B cells were exposed to QA (100µM) for 1 hour and kynurenine pathway enzymes, antiviral and inflammatory responses were evaluated after 6 or 24 h post-infection by RT-qPCR and cytokine assays by ELISA. Viral infection stimulated some kynurenine enzymes expression at day 7 post infection and these effects are accentuated with CSE pre-exposure. QA addition altered the gene expression of several antiviral molecules such as RIGi and IFNb at 24 h post infection, but also altered inflammation with an impact on IL6 and IL8 expression and secretion. These effects could be passed by QA himself, or by NAD production following QA degradation. The stimulation of the kynurenine pathway by viruses is modified by CS with a potential upgreat of QA concentration. In this context, QA modulates the inflammatory and the antiviral response in the airway epithelium, and may play a role in COPD exacerbations.