key: cord-0952614-cvrwvp2j authors: Raucci, Federica; Mansour, Adel Abo; Casillo, Gian Marco; Saviano, Anella; Caso, Francesco; Scarpa, Raffaele; Mascolo, Nicola; Iqbal, Asif Jilani; Maione, Francesco title: Interleukin-17A (IL-17A), a key molecule of innate and adaptive immunity, and its potential involvement in COVID-19-related thrombotic and vascular mechanisms date: 2020-05-03 journal: Autoimmun Rev DOI: 10.1016/j.autrev.2020.102572 sha: e9a96e59a87740df919268e2b142602f2c85ea19 doc_id: 952614 cord_uid: cvrwvp2j nan Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by severe acute respiratory syndrome (SARS) which first appeared in Wuhan, China, December 2019, and has since spread globally [1] . To date, official figures released by World Health Organization (WHO), indicate over 3 million cases worldwide with over 200,000 deaths. However, the number of newly diagnosed patients has started to decline, suggesting that the rate of transmission is beginning to be controlled by countries [2] . Although most patients have mild symptoms and good prognosis after infection, some develop severe symptoms and die due to multiple organ failure [3] [4] [5] . Based on the published literature and clinical observations, researchers and clinicians around the world have postulated about the pathogenesis of this viral infection in humans. We know that the virus has the capacity to cross mucous membranes (especially nasal and larynx mucosa), and in severe cases leads to multiple systemic manifestations and pneumonia requiring mechanical ventilation [6] . Interestingly, COVID-19 disease prognosis is strongly correlated to clinical characteristics of patients, with high risk associated to those with a concomitance of cardiovascular risk factors, primarily obesity, hypertension, and diabetes mellitus [4, 7] . In the context of COVID-19associated cardiovascular manifestations, more recent studies report that the disease is commonly complicated with coagulopathy linked to disseminated intravascular coagulation (DIC) and/or thrombotic and thromboembolic disease [4, 8, 9] . For these reasons, many patients with severe COVID-19 meet the Third International Consensus Definitions for Sepsis (SEPSIS-3) [10] . Moreover, we must consider that the development of thrombotic and thromboembolic disease could be a direct consequence of the systemic inflammatory process related to interleukin (IL)-6 and IL-17A upregulation [11] [12] [13] [14] . This clinical scenario has prompted the use of intravenous immunoglobulin (IVIG) and low molecular weight heparin (LMWH) anticoagulant therapy as early as possible, particularly when circulating T and B cells numbers decrease, and inflammatory cytokines and D-Dimer (a non-specific parameter of thrombi formation) increase abnormally [15] [16] [17] . While IVIG has shown efficacy in the treatment of patients with influenza and SARS, more clinical data is required, for both IVIG and LMWH, to confirm significant efficacy in COVID-19 patients [18] [19] [20] . Viral infection and subsequent systemic and/or local inflammation is a common cause of DIC [21] [22] [23] due to increased synthesis of cytokines such as as tumor necrosis factor-α (TNF-α), IL-1β, IL-6, IL-17A and IL-18 [24] . IL-17A (commonly known as IL-17) is the most studied member of the IL-17 cytokine family. It is produced by T-helper (Th)-17 lymphocytes, and by innate cellular components [25, 26] . This "unique" proinflammatory cytokine, highly produced and modulated in patients with chronic inflammatory-based diseases, also plays a role in the cardiovascular system, more specifically, it is involved in cardiovascular complications associated with autoimmune and inflammatorybased diseases [27] . Indeed, in the attempt to find a link between inflammatory markers and endothelial dysfunction, Marder et al., [28] demonstrated that elevated IL-17A levels strongly correlated with vascular dysfunction in subjects affected by rheumatoid arthritis. Furthermore, it has been shown that, human umbilical vein endothelial cells (HUVECs), treated with IL-17A, synergistically with TNF-α, induces tissue factor (TF) expression and modulates thrombomodulin [29] and thrombosis formation [30, 31] . In addition to IL-17A role on the vascular endothelium, data, from our research group and others has also highlighted a role for this cytokine in platelet biology. We previously reported IL-17A ability to increase, in both mouse and human, platelet activation [32] and to modulate, in vivo, arterial thrombus formation [33] through the extracellular signal-regulated kinase-2 (ERK-2) signaling pathway [34] . Moreover, a study from Ding et al., [35] investigated the role of IL-17A in mouse and human deep vein thrombosis (DVT) formation, and found that this cytokine promotes DVT pathogenesis by enhancing platelet activation/aggregation, neutrophil infiltration, and endothelial cell (EC) activation. Collectively, these data suggest that the use of an anti-IL-17A neutralising monoclonal antibody may be useful for DVT-related syndromes. Taking all these various pieces of evidence (albeit minimal), we would like to hypothesize that in COVID-19 patients, IL-17A could potentially promote a pro-thrombotic state in the vascular system. Indeed, the increased level of this cytokine in COVID-19 infection would not be, per se, a stimulus for thrombogenesis but, most likely, support platelet aggregate formation at sites of vascular injury (Fig. 1) . Based on these assumptions, it would be fascinating to characterize IL-17 levels in bronchoalveolar lavage fluid (BALF) and plasma/serum samples of mild-and severe-infected COVID-19 patients, and potentially go on to test the efficacy of antibodies targeting IL-17A (alone or in a sequential therapy with anti-IL-6 agents) for the treatment of thrombotic, as well respiratory and systemic manifestations of severe COVID-19. These could be useful not only for new therapeutic strategies but also for improving our understanding of the etiopathogenesis and genetic susceptibility of COVID-19 infection. This article has been conducted and written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Functional specialization of interleukin-17 family members Commentary: IL-17 in chronic inflammation: from discovery to targeting 17 as a novel predictor of vascular function in rheumatoid arthritis Combination of IL-17 and TNFα induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells Modeling of the effects of IL-17 and TNF-α on endothelial cells and thrombus growth Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction IL-17A increases ADP-induced platelet aggregation Interleukin-17A exacerbates ferric chloride-induced arterial thrombosis in rat carotid artery IL-17A facilitates platelet function through the ERK2 signaling pathway in patients with acute coronary syndrome IL-17A promotes the formation of deep vein thrombosis in a mouse model This work was in part supported by MIUR (PRIN 2017; 2017A95NCJ/2017A95NCJ_002, "Stolen molecules -Stealing natural products from the depot and reselling them as new drug candidates"). AJI is supported by Birmingham Fellowship and AAM by a Saudi Government/KKU scholarship.