Autoimmunity Reviews xxx (xxxx) xxxx Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Interleukin-17A (IL-17A), a key molecule of innate and adaptive immunity, and its potential involvement in COVID-19-related thrombotic and vascular mechanisms Federica Rauccia,1, Adel Abo Mansourb,c,1, Gian Marco Casilloa, Anella Savianoa, ⁎ ⁎ Francesco Casod, Raffaele Scarpad, Nicola Mascoloa, Asif Jilani Iqbalb,a, , Francesco Maionea, a ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Guraiger, Abha 62529, Saudi Arabia d Rheumatology Research Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, via S. Pansini 5, 80131 Naples, Italy b c A R T I C LE I N FO Keywords: COVID-19 IL-17A Platelet Thrombus Vascular diseases 1. Introduction 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 [3–5]. 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 [11–14]. 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 [15–17]. While IVIG has shown efficacy in the treatment of patients with influenza and SARS, more clinical data is required, for Abbreviations: COVID-19, Coronavirus disease 2019; DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; EC, endothelial cells; ERK-2, extracellular signal regulated kinase-2; HUVECs, human umbilical vein endothelial cells; IL-, interleukin-; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin; SARS, severe acute respiratory syndrome; SEPSIS-3, Third International Consensus Definitions for Sepsis; TF, tissue factor; Th-, T-helper; TNF-α, tumor necrosis factor-α; WHO, World Health Organization. ⁎ Corresponding authors. E-mail addresses: A.J.Iqbal@bham.ac.uk (A.J. Iqbal), francesco.maione@unina.it (F. Maione). 1 These authors share first co-authorship. https://doi.org/10.1016/j.autrev.2020.102572 Received 23 April 2020; Accepted 25 April 2020 1568-9972/ © 2020 Elsevier B.V. All rights reserved. Please cite this article as: Federica Raucci, et al., Autoimmunity Reviews, https://doi.org/10.1016/j.autrev.2020.102572 Autoimmunity Reviews xxx (xxxx) xxxx F. Raucci, et al. Fig. 1. Schematic representation of inflammatory pathways (left part) involved in the COVID-19-related respiratory syndrome. The inflammatory scenario induced by COVID-19 has cardiovascular implications (right part, top panel) in terms of Th-1/Th-17/T-reg balance that favors the production of IL-17A. The overproduction of this cytokine (right part, bottom panel) amplifies platelet hyper-reactivity and thrombus formation. 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 antiIL-17A neutralising monoclonal antibody may be useful for DVT-related syndromes. both IVIG and LMWH, to confirm significant efficacy in COVID-19 patients [18–20]. 2. IL-17A and COVID-19-related thrombotic and vascular mechanisms Viral infection and subsequent systemic and/or local inflammation is a common cause of DIC [21–23] 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 3. Discussion 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 IL17 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. 2 Autoimmunity Reviews xxx (xxxx) xxxx F. Raucci, et al. Author contributions [14] FR, AAM, GMC and AS drafted the manuscript. FC, RS, NM, AJI and FM wrote and revised the manuscript. All Authors gave final approval to the publication. [15] Declaration of Competing Interest [16] 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. [17] Acknowledgments [18] 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. 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