Interleukin-17A (IL-17A), a key molecule of innate and adaptive immunity, and its potential involvement in COVID-19-related thrombotic and vascular mechanisms

Since 2003, outbreaks of Coronavirus have caused multiple public health epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The first case of infection in response to a new strain of Coronaviridae, designated Coronavirus disease-19 (COVID-19) was recorded in Wuhan, China [1]. This virus appears to be weaker than SARS, in terms of pathogenesis but more sustained in its transmission behavior [2]. COVID-19 is transmitted through droplet inhalation, saliva, nasal and mucous membranes of eyes. Symptoms include fever, continuous coughing and shortness of breath. This has been shown to lead to a mild or severe respiratory illness and, in a number of cases, death. However, this is largely dependent upon the health status of the patient, with highest risk associated with those who have pre-existing respiratory tract pathologies [3]. As of April 2, 2020, the World Health Organization (WHO) reported 896,450 cases of COVID-19 and 45,525 deaths worldwide. The number is growing, and urgent clinical strategies are needed [supplementary materials 1].The pathological presentation following COVID-19 infection in severe cases [supplementary materials 2] includes specific modulation and release, mainly by lung epithelial cells, of pro-inflammatory cytokines, such as interleukin-(IL-)6, IL-1β and tumor necrosis factor-α (TNF-α) which contribute to lung damage by further aggravating clinical features, such as pneumonia severity in patients affected by this virus [4].From a cellular viewpoint, lung epithelial cells play a crucial role locally in the release of several pro-inflammatory cytokines such as IL-8 and IL-6. Recent studies have shown that the production of these mediators is regulated at the transcriptional level. Indeed, human lung epithelial cells turn from normo-responsive to hyper-responsive IL-8 and IL-6-producing cells

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Background and Purpose Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE2 synthase (mPGES) and PPAR‐γ expression are modulated by a variety of inflammatory factors and stimuli. Considering that very little is known about the biological effects promoted by IL‐17 in the context of mPGES‐1/PPAR‐γ modulation, we sought to investigate the contribution of this unique cytokine on this integrated pathway during the onset of inflammation. Experimental Approach We evaluated effects of PF 9184 (mPGES‐1 inhibitor) and troglitazone (PPAR‐γ agonist) in vitro, using the mouse macrophage cell line J774A.1. In vivo, the dorsal air pouch model in CD1 mice was used, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto‐chemokines and PGs were assessed using elisa assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways. Key Results PF 9184 and troglitazone, in a time‐ and dose‐dependent manner, modulated leukocyte infiltration, myeloperoxidase activity, and the expression of COX‐2/mPGES‐1, NF‐кB/IкB‐α, and mPTGDS‐1/PPAR‐γ, induced by IL‐17. Moreover, both PF 9184 and troglitazone modulated PG (PGE2, PGD2, and PGJ2) production, the expression of different pro‐inflammatory cyto‐chemokines, and the recruitment of inflammatory monocytes, in response to IL‐17. Conclusions and Implications Our data suggest that IL‐17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. The results of this study show, for the first time, that the IL‐17/mPGES‐1/PPAR‐γ pathway could represent a potential therapeutic target for inflammatory‐based and immune‐mediated diseases. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc