The IL-17 family of cytokines has 6 members, from IL-17A to IL-17F, all of them being involved in the response against infections by pathogens and in chronic autoimmune and inflammatory diseases,15 being the cytokine IL-17A the most studied within the group. This family of cytokines has highly conserved sequences in mammals, such that between the human and murine isoforms of IL-17 there is a sequence homology between 62% in IL-17A and 88% in IL-17B.16 The two members with the highest homology to each other are IL-17A and IL-17F, which can form heterodimers.17 IL-17A, initially called human cytotoxic antigen associated with T-8 lymphocytes, was isolated for the first time in 1993 from a T-cell hybridoma. Although analysis of its cDNA showed that it had some homology with a gene for Herpesvirus samiri, was classified within the group of cytokines because it has an unstable sequence rich in adenylate-uridylate in the 3′UTR region since it is capable of inducing the synthesis of cytokines.18 At the molecular level, IL-17A is a glycoprotein of 155 amino acids and with a molecular weight of 35 kDa, although in general it gives rise to the formation of homodimers linked together by a disulfide bridge.16,19 IL-17 cytokines activate receptors of the same family, the IL-17Rs that consist of 5 members, named IL-17RA through IL-17RE, and that can also form homo- and heterodimers with each other. Thus, IL-17RA is present in most of the dimers that are formed, and in a great diversity of cell types, mostly in immune cells, but the rest of the receptors are specific to specific cell types.20 Likewise, there are also differences in terms of ligand-receptor affinity between the different members, with IL-17A binding with greater affinity to IL-17RA, while IL-17F preferentially binds to IL-17RC.19,21 These affinity differences could help explain the great variability in responses elicited by this versatile family of cytokines.

The first cells described capable of producing IL-17A were Th17 lymphocytes (CD4+/IL-17A + cells). In general, CD4 + T lymphocytes actively participate in the immune response, in such a way that after antigenic stimulation, naive CD4 + lymphocytes are activated, and they expand and differentiate into the different subpopulations known as T helper (Th).22 Within these Th subpopulations, the effector subtypes Th1, Th2, Th9, Th17, Th22 and follicular Th (Thf) are included, as well as the regulatory T lymphocyte subtype, called Treg, thus broadening the classic view of only two subtypes. Th (Th1 and Th2).23,24 Each Th subtype is classified based on the specific pattern of cytokines that they produce and the different markers that they express.23,24 However, there is great plasticity between the different subtypes, with intermediate cellular phenotypes that are the subject of research, but also controversy.25–28 Differentiation to each Th subtype is driven by a specific combination of cytokines that activate specific transcription factors.29–32 Here, the specific combination of the proinflammatory cytokines IL-1 β, IL-6 IL-21 and or TGF-β1 regulates the differentiation of human naive T lymphocytes to Th17 phenotype. This differentiation is regulated by the activation of both the ROR factor γt (Retinoid related Orphan Receptor γt) and the STAT3 protein (Signal Transducer and Activator of Transcription 3) leading to gene transcription controlling the phenotypic transition to Th17, such as the IL-23R33–37 gene. Once differentiated, Th17 cells mostly secrete IL-17A, but they can also produce IL-22, IL-26 and IL-23, which help stabilize the lineage, or release chemokines that contain the CC motif, such as the chemokine ligand-20 (CCL-20)29,30,33,38,39 (Fig. 1). With this secretion pattern, Th17 cells have as their main function the defense against pathogens in infectious diseases, but they also participate in the pathogenesis of various inflammatory diseases and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, or chronic inflammatory diseases, including atherosclerosis and hypertension.40–43 In this sense, several factors related to cardiovascular and renal damage, such as the cytokine IL-6, Angiotensin II (Ang II), TGF-β1, or CTGF/CCN2 (connective tissue growth factor/cellular communication network2) participate in the generation of Th17 cells.44–46 IL-17A is produced by cells other than Th17, including γδ lymphocytes (Fig. 1), and probably also by neutrophils, invariant natural killer T cells, CD8 + cells, innate lymphoid cells, and mast cells, although in some Of these cells, there is controversy as to whether they are only capable of storing IL-17A but not producing it, as could be the case with mast cells.30,37,47,48

Fig. 1.

IL-17A producing cells. In hypertensive situations, an increase in inflammatory cytokines and immune cell activation has been described that can contribute to the production of IL-17A.

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IL-17A generates pro-inflammatory responses that can vary substantially depending on the cell type and pathological conditions.9,10,11,13,49–54 One of the first evidences of the involvement of IL-17A in the inflammatory response showed that in cultured synoviocytes from patients with rheumatoid arthritis, IL-17A increased the levels of IL-6 and IL-8.54 Subsequently, it was observed that IL-17A induced responses in various immune cells, regulating various functions, such as monocyte chemotaxis, and increased production of pro-inflammatory mediators, thus helping to amplify the inflammatory response in damaged tissues11,52,53,55,56 (Fig. 2). The actions of IL-17A in the cells of the immune system are not completely clarified, and it may also participate in the change of macrophage phenotypes,57 and induce the degradation of extracellular matrix by neutrophils, through the regulation of metalloproteinases (MMPs).58

Fig. 2.

Effects of IL-17A production by lymphocytes (Th17 and γδT) on immune cells and on the tissue inflammatory response.

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Inflammation is defined as a non-specific response suffered by a tissue to an attack produced by different mechanical, chemical or biological factors, and whose purpose is to suppress the agent causing the damage and repair the damaged tissue.82 Epidemiological studies have shown that there is an important connection between different chronic inflammatory diseases and cardiovascular diseases. In this sense, the incidence of myocardial infarction is increased in patients with rheumatoid arthritis, systemic lupus erythematosus, or psoriasis.83 These data contribute to highlighting the importance of the inflammatory response in the development and progression of various vascular pathologies, such as vasculitis, aneurysms, hypertension or atherosclerosis.83,84

Recent studies have evaluated the role of vascular inflammation and of specific cytokines and chemokines (eg MCP-1, IL-8, IP-10, and IL-17A) in the onset and development of endothelial dysfunction associated with hypertension.85 IL-17A is a key cytokine in the inflammatory response, included in the cardiovascular system (Fig. 2). In fact, the stimulation with IL-17A increases the expression of multiple pro-inflammatory genes, including mcp-1 and il-6, in cultured murine vascular smooth muscle cells (VSMCs).79 Similarly, IL-17A enhances the pro-inflammatory effect of other cytokines on endothelial cells, VSMCs and macrophages.86 Supporting these findings, the genetic deficiency of IL-17A decreased the inflammatory infiltrate in the murine aortic wall to normal levels.41

Major proinflammatory mechanisms activated by IL-17A include the production of reactive oxygen species (ROS), of nitric oxide (NO), the activation of the transcription factor factor nuclear kappa B (NF-κB) and regulation of various signaling cascades associated with protein kinases, such as RhoA/Rho-kinase, mitogen-activated protein kinases (MAPKs) or Akt2,14,52,53,55,65,76,78,87 (Fig. 4). NF-κB is a key molecule in the regulation of the inflammatory response, and also in vascular remodeling.88 Activation of this transcription factor has been linked to cardiovascular damage in hypertension, atherosclerosis, cardiac hypertrophy, myocardial infarction or aneurysms formation.88–92 In human umbilical cord endothelial cells (HUVEC) in coculture with T cells (Jurkat cells) IL-17A facilitates endothelial inflammation, by inducing the expression of adhesion molecules ICAM-1 and VCAM-1 and chemokines CCL-20 and CXCR-4 in endothelial cells mediated by ERK1/2 phosphorylation, and therefore promotes the adherence of T cells to HUVEC87 (Fig. 4). A recent study has shown that the overexpression of IL-17A in T cells in mice causes an increase in the production of ROS in circulating cells, vascular dysfunction and perivascular fibrosis compared to control mice.93

Fig. 4.

Molecular mechanisms regulated by IL-17A in vascular smooth muscle cells and in endothelial cells.

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Lately it has been shown that the TLR-4 receptor (Toll-like receptor 4) participates in hypertension94 and in the regulation of experimental inflammation in the kidney.95,96 In this sense, mice deficient in TLR-4 are partially protected from AngII-induced blood pressure elevation and the overproduction of ROS, macrophage infiltration and the expression of MCP-1 in the kidney.97 Interestingly, IL-17A blockade considerably decreased renal TLR-4 mRNA overexpression induced by Ang II infusion in mice, suggesting an interconnection between IL-17A and TLR-4 in the regulation of hypertension and kidney injury triggered by Ang II.65

IL-17A induces endothelial dysfunction and oxidative stress, through the intracellular RhoA/Rho-kinase (ROCK) signaling pathway, by phosphorylating threonine residue 495 of endothelial nitric oxide synthase (eNOS Thr495) in mouse aorta76,78,98,99 (Fig. 4). Furthermore, IL-17A deficient mice are protected of AngII-induced blood pressure elevation, endothelial dysfunction, evaluated by vascular reactivity experiments, and ROS overproduction .41 RhoA pathway/Rho kinase and regulation of NO contribute to IL-17A-mediated hypertension. Some data also support the involvement of IL-17A in preeclampsia and autoimmune diseases associated with hypertension, such as systemic lupus erythematosus and chronic rejection of the allograft.76 Conditional dermal overexpression of IL-17A in keratinocytes is characterized by increased systolic blood pressure associated to systemic endothelial dysfunction, increased ROS formation, elevated circulating inflammatory leukocytes CD11b+ left ventricular hypertrophy, and reduced survival compared to control mice.78 In endothelial cells, IL-17A activates the expression of eNOS and cyclooxygenase-2 (COX-2) and this is associated with angiogenesis, determined as proliferation, apoptosis, migration and tubulogenesis.100

Arterial stiffness and the accumulation of extracellular matrix (ECM) can contribute to vascular remodeling and it can be the cause or the consequence of hypertension, and this issue is still highly controversial.101 Studies on the effect of IL-17A modulation on vascular fibrosis provided variable results. The systemic adminstration of IL-17A in mice induced functional and structural changes in mesenteric resistance arteries (MRAs) in vivo characterized by increased intrinsic vascular stiffness (independent of vessel geometry), which could contribute to the increase in blood pressure, but did not modify the three-dimensional structure of elastin nor the levels of collagens, the main components of ECM in MRAs.79 Along the same lines, and supporting the absence of a profibrotic effect of IL-17A at the vascular level, in experimental stenosis due to partial ligation of the carotid artery characterized by vascular remodeling and increased ECM proteins, the IL-17A gene deletion does not change the percentage of stenosis but it did reduce the exterior remodeling.98 Furthermore, the deletion of IL-17A in experimental atherosclerosis in Apolipoprotein E (ApoE) deficient mice did not modify the area of ​​atherosclerotic plaques or the levels of ECM proteins, such as elastin and collagen.98 Regarding the vascular stiffness induced by the systemic administration of Ang II, IL-17A blockade did not improve the stiffness in the MRAs after 2 weeks of infusion,79 but the gene deletion of IL-17A reversed the changes in stiffness induced by Ang II in the aorta at times longer than 4 weeks.102 At the cellular level, IL-17A did not modify the gene expression of profibrotic factors or ECM components in cultured VSMCs79 (Fig. 4). However, studies in aortic fibroblast cultures showed that IL-17A induces the expression of the collagen gene 3a1.102 Studies in mice deficient in cells γδT or antibodies γδT in the model of AngII-induced hypertension showed lower IL-17A production in the in the heart associated with less cardiac fibrosis .75 In summary, various studies have shown contradictory effects of IL-17A on fibrosis, suggesting that this cytokine has different actions depending on the cell type and the pathology involved.103

IL-17A regulates cell growth in cultured cells, although the effect depends on the cell type. Thus, while IL-17A induces apoptosis in cardiomyocytes,104 it has been postulated as a proliferative and migratory factor in VSMCs,79,105 fibroblasts106 and endothelial cells107. In a context of a tumor microenvironment, IL-17A triggered cell proliferation and epithelial to mesenchymal transition (EMT), evidenced mainly by the inhibition of epithelial markers, such as E-cadherin, and the increase of mesenchymal markers, such as vimentin.108 In this sense, some preclinical studies, in human prostate cancer cell lines109 and in mice treated with a neutralizing anti-IL-17A antibody,110 demonstrated the crucial participation of IL-17A in the development of EMT. Recently, IL-17A produced by neutrophils has been implicated in the progression of gastric cancer by inducing EMT via JAK / STAT3 pathway activation.111 The active participation of IL-17A in cell cycle modulation in a tumor context suggests that it could also trigger effects in a physiological environment. In cultured tubular cells, the role of IL-17A in the regulation of the cellular phenotype, specifically patial EMT has been confirmed, which may contribute to tubulointerstitial fibrosis.109,112 At the vascular level, remodeling involves changes in the VSMCs with a phenotypic transition from the classic contractile cell type to a poorly contractile phenotype, known as the synthetic type. These cellular transformations are associated with changes in the levels of a series of proteins, both cellular and of the secretome, that are characteristic of each phenotype.101,113 In in vivo studies, IL-17A modifies calponin expression in VSMCs of AMRs, which reflects a change in the cellular phenotype79 (Fig. 5). Although it has been classically considered that arterial stiffness is a consequence of increased ECM, mainly due to accumulation of collagen, it has recently been shown that stiffness can also appear in the absence of fibrosis, in this case being regulated by proteins that control contractility of the VSMCs and cell-ECM interactions, including calponin.101 Calponin is an actin-binding protein that regulates contractile functions and stabilization of stress fibers in VSMCs114 and is decreased in various models of hypertrophic vascular remodeling.115,116 The decrease in calponin levels in the vascular cells of the MRAs induced by IL-17A could contribute to increasing vascular stiffness and blood pressure (Fig. 4).

Fig. 5.

Potential explanation of the effect of IL-17A on the regulation of blood pressure. Effect on resistance mesenteric arteries.

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On the other hand, it is important to point out the role that IL-17A plays in promoting the senescence of endothelial cells cultured117 (Fig. 4) and in vivo, according to results obtained in knockout mice for IL-17A or for its receptor.118 Thus, recently, it has been described that a neutralizing antibody to IL-17 reduced the expression of the senescence marker Cdkn1a.119

The mechanisms that regulate blood pressure are complex, and involve the participation of different organs and systems. One of the mechanisms that contribute to hypertension is the appearance of structural and functional changes in the arteries (a process known as vascular remodeling), such as a reduction in the diameter of the vessel lumen or an increase in the ratio between the middle layer and the lumen, generating an increase in the pressure exerted by the blood on the wall of the vessels. Vascular remodeling depends on cellular processes such as cell growth, hypertrophy of VSMCs or the overproduction of ECM proteins, such as collagen and fibronectin.120–122 Specifically, remodeling of small-caliber arteries or arterioles participates in the pathogenesis of HT. The vascular remodeling of the MRAs in patients with essential hypertension is characterized by an increase in the thickness of the vascular wall, the mean/lumen ratio and the stiffness of the wall. These changes increase peripheral vascular resistance by increasing blood pressure.123–125 Most of the preclinical studies that have evaluated the role of IL-17A in experimental hypertension have focused on the study of structural and functional changes in the aorta.41,76,78 However, the changes in the aorta would not be enough to explain the increase in blood pressure, suggesting that they could be a consequence of the hypertension itself. In this sense, IL-17A participates in the vascular remodeling ofMRAs, suggesting that this cytokine could be a causative factor of hypertension.79 In mice, the systemic administration of IL-17A to increase circulating levels of IL-17A to values ​​similar to those observed in prehypertensive patients causes an increase in blood pressure associated with structural and functional changes in MRAs, characterized by hypertrophic rinward remodelling and an increase in arterial stiffness.79 In addition, a combination therapy of hydralazine and hydrochlorothiazide, administered when IL-17A had already induced an increase in blood pressure, was able to lower blood pressure, but not to reverse the changes in the mechanical and structural properties of the MRAs induced by IL-17A, suggesting a direct effect of IL-17A on MRAs. Supporting this hypothesis, we demonstrated that a neutralizing antibody to IL-17A normalized vascular remodeling in MRAs induced by systemic administration of Ang II.79 These preclinical studies suggest that the changes induced by IL-17A in the small arteries could be responsible, at least in part, for the increase in blood pressure, demonstrating a new mechanism with which IL-17A could contribute to the development of hypertension (Fig. 5).