MINI REVIEW published: 01 April 2021 doi: 10.3389/fimmu.2021.625181 The Dual Role of Platelets in the Cardiovascular Risk of Chronic Inflammation Carlos Zamora, Elisabet Cantó and Sílvia Vidal* Inflammatory Diseases, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain Patients with chronic inflammatory diseases often exhibit cardiovascular risk. This risk is associated with the systemic inflammation that persists in these patients, causing a sustained endothelial activation. Different mechanisms have been considered responsible for this systemic inflammation, among which activated platelets have been regarded as a major player. However, in recent years, the role of platelets has become controversial. Not only can this subcellular component release pro- and anti-inflammatory mediators, but it can also bind to different subsets of circulating lymphocytes, monocytes and neutrophils modulating their function in either direction. How platelets exert this dual role is not yet fully understood. Keywords: platelet, chronic inflammation, cardiovascular risk, leukocytes, systemic inflammation Edited by: Eva Reali, University of Milano-Bicocca, Italy INTRODUCTION Reviewed by: Systemic inflammation (SI) has been described as a consequence of increased levels of the Cristiana Barbati, circulating pro-inflammatory mediators that activate endothelial cells (EC). Endothelial activation Sapienza University of Rome, Italy Angelo A. Manfredi, is part of a normal immune system defense, but a prolonged inflammatory stimulus induces Vita-Salute San Raffaele a sustained endothelial activation/dysfunction that is often associated with atherogenesis and University, Italy cardiovascular events. The role of SI on cardiovascular (CV) risk has been explored in autoimmune *Correspondence: diseases. Systemic lupus erythematosus (SLE)-like mouse models display endothelial dysfunction Sílvia Vidal and cardiac hypertrophy, mediated through IL-6 and IL-1α (1). In these patients, it has been shown svidal@santpau.cat that B lymphocyte stimulator induced apoptosis of endothelial progenitors cells and EC (2). In addition, it has been suggested that autoantibodies play a role in endothelial dysfunction, possibly Specialty section: by modulating the adhesion of neutrophils (3, 4). In a model of arthritis, endothelial dysfunction This article was submitted to was only observed in rats with a persisting imbalance between NOS and COX-2 pathways, higher Inflammation, plasma levels of IL-1β and tumor necrosis factor-α (TNF-α) (5). The presence of diabetes mellitus a section of the journal type 2 in patients with metabolic syndrome impairs the endothelial function (6). In a model of SI, Frontiers in Immunology the levels of endothelin-1 and endocan are related to endothelial dysfunction (7). However, there Received: 02 November 2020 are some circumstances in which the relationship between SI and endothelial dysfunction is less Accepted: 15 February 2021 clear. In Systemic Inflammatory Response syndrome, the levels of dysfunctional EC were associated Published: 01 April 2021 with mortality and organ dysfunction independently of inflammatory markers (8). Citation: The link between inflammation and endothelial dysfunction has been confirmed by the Zamora C, Cantó E and Vidal S (2021) inhibition of molecules related to SI. Anti-TNFα antibodies reduces sE-selectin and sVCAM The Dual Role of Platelets in the Cardiovascular Risk of Chronic expression (9) and decreases endothelium-dependent relaxation (10, 11). EC treated with Inflammation. etanercept revert the apoptosis induced by TNF-α (12). JAK inhibitors improve endothelium Front. Immunol. 12:625181. dependent vasorelaxation, endothelial cell differentiation and lipoprotein profiles, while decreasing doi: 10.3389/fimmu.2021.625181 pro-inflammatory cytokines in SLE-like syndrome (13). Glucocorticoids decrease IL-1β and TNF-α Frontiers in Immunology | www.frontiersin.org 1 April 2021 | Volume 12 | Article 625181 Zamora et al. Platelets in Cardiovascular Risk levels, improving the function of endothelium in rheumatoid (miRNA) and epigenetic modifications. The overexpression of arthritis (RA) (14). Patients with CV risk factors had miR100 in ECs attenuates leukocyte-endothelial interaction, increased levels of IL-1β and its gene expression signature represses the mammalian target of rapamycin complex 1 and blocking IL-1β with canakinumab was observed to signaling, stimulating endothelial autophagy, and attenuates NF- prevent recurrent cardiovascular disease (CVD) (15). Agents κB signaling. Local miR100 expression is inversely correlated with nucleoside triphosphate hydrolase activity decrease with an inflammatory cell content (28). miR181b inhibits platelet-leukocyte-endothelium interaction, the transcription of downstream and upstream NF-κB signaling in response to pro-inflammatory cytokines, microvascular platelet-neutrophil activation (29), while the NF-κB target genes (VCAM-1, ICAM- aggregate sequestration, activation marker expression on 1, E-selectin, and tissue factor) (30) and miR223 are associated platelets (PLTs) and neutrophils contained in these aggregates, with HUVEC dysfunction (31). Additionally, IFN-α, through leukocyte extravasation, and organ damage (16). Furthermore, miR155, promotes an endothelial dysfunction signature in dihydroartemisin inhibits the occludin downregulation induced HUVECs characterized by transcription suppression and the by TNF-α, improving the permeability of EC (17) and the mRNA instability of eNOS and by the upregulation of MCP-1 and inhibition of cannabinoid receptors reduces leukocyte-adhesion VCAM-1 and enhanced neutrophil adhesion (32). and improves microvascular blood flow (18). The pre-treatment Endothelial microparticles (MPs), shed as a result of of primary cultured human umbilical vein endothelial cells the activation of EC are considered a source of important (HUVECs) with sevoflurane reduces ICAM-1 (intercellular information on the status of ECs and vascular function (33, 34). adhesion molecule-1) and VCAM-1 (vascular cell adhesion Circulating levels of endothelial MPs reflect a balance between molecule-1) IκBα, and NF-κB activation, and blocks the cell stimulation, proliferation, apoptosis, and cell death (35) and adhesion of leukocytes (19). are increased by inflammatory stimuli, mediated by the activation Products with anti-inflammatory properties can improve of NF-κB and associated with oxidative stress intensity (36, 37). endothelial function. Lactobacillus plantarum 299v supplements Endothelial MPs are increased in autoimmune diseases (38) and decreased inflammatory markers (20), while the active form serve as markers for vascular dysfunction and their effects depend of vitamin D diminishes IL-6 secretion and increases the on their cargo and on the surface molecules. Recently, levels of angiogenic capacity of myeloid angiogenic cells via CXCL10 endothelial MPs have been associated with disease activity in SLE down-regulation (21). patients and CV risk (39). MPs from RA patients had higher expression of TNF-α on the surface compared to healthy donors (HD), increasing apoptosis FEATURES OF ENDOTHELIAL and autophagy levels on EC and correlating with clinical RA DYSFUNCTION activity (40). The inflammatory phase that leads to endothelial dysfunction is initiated by TNF-α and subsequently amplified by IL-1, IL-6 and downstream mediators. Endothelial dysfunction refers to PLATELETS AND SYSTEMIC the failure by ECs to perform their physiological functions, INFLAMMATION often due to a maladaptive response to pathological stimuli. The phenotypic features of endothelial dysfunction include PLTs have come to be recognized as active players in SI. After the upregulated expression of endothelial leukocyte adhesion activation, PLTs participate in the vasculature inflammation and molecules (ELAMs) [E-selectin, ICAM-1 and VCAM-1]. damage, atherogenesis and thrombosis (41–45). Wide ranges of On leukocytes, activated ECs induce the affinity of counter- stimulus are able to activate PLTs. The strong PLT activation was receptors for ELAMs and secrete and display chemokines on achieved with the ligation of the agonist thrombin, collagen and the luminal surface. Endothelial dysfunction also includes a ADP to the PLTs receptors: protease-activated receptor 1, GPVI compromised barrier function, the secretion of microvesicles, and P2Y1 or P2Y12 respectively (46–48). Other non-classical an increased vascular smooth muscle tone, and the increased pathways are able to activate PLTs due to the expression of Toll- production of vasoconstrictor substances, the reduced resistance like receptors (TLR), TNF-α receptor, IL-1β receptors and C-type to thrombosis via platelet aggregation and oxidative stress lectin-like receptors (49–53). Some autoantibodies presents in upregulation (22–24). It was described that high levels of IL-8 and autoimmune disease patients such as anti-citrullinated protein, TNF-α up-regulate CX3CR1 expression on platelet-monocyte anti-β2 glycoprotein I and anti-D4GDI have also the ability to aggregates, increasing adhesion to activated endothelium induce PLT activation through FCγRIIa (54–56). (25). In mouse models, increased IL-17 was associated with However, PLTs also participate in the resolution of reactive oxygen species formation, circulating inflammatory inflammation as anti-inflammatory elements. How PLTs leukocytes and endothelial dysfunction (26), while higher sense the signal to exert pro- or anti-inflammatory functions levels of resistin, TNF-α, IL-1β, and MMP-9 expression were is not yet fully known. However, it is known that PLTs exert associated with the levels of inflammatory infiltrates in artery their functions by releasing soluble factors and interacting walls (27). with cells. The dual role of PLTs in inflammation (57, 58) may Beyond the activation of the well-known signaling cascades, be the result of differences in the PLT packing of molecules, the stimulation of EC induces gene expression via microRNAs activated-dependent release by different stimuli, the kinetics of Frontiers in Immunology | www.frontiersin.org 2 April 2021 | Volume 12 | Article 625181 Zamora et al. Platelets in Cardiovascular Risk TABLE 1 | Evidences of dual role of expressed/secreted platelet factors. blocking reduces the inflammation of vasculature and CV events by reducing leukocyte recruitment and the generation Factor Pro-inflammatory Anti-inflammatory of neutrophil extracellular traps (NETs) by neutrophils (60, 81, PF4 • Monocytes: • T lymphocytes: 82). ↑ phagocytosis (59) ↓proliferation (61) PF4 also acts as an anti-inflammatory factor on T lymphocytes ↑ respiratory burst (59) ↓Th17 differentiation (62) (83), limiting Th17 differentiation by suppressing RORγ ↑ pro-inflammatory ↓granzyme B (61) expression (62). A lack of PF4 induces the rejection of cytokines (59) • Neutrophils: cardiac transplantation by increasing levels of IL-17 and T cell ↑ NETs formation (60) mediated inflammation. We has observed that PF4 decreases T • Endothelial cells: lymphocyte proliferation and granzyme B expression in CD8+ ↑ Leukocyte recruitment (60) T lymphocytes (61), explaining how higher levels of PF4 in a IL-1 ↑ endothelial activation (63, 64) malignant context can limit T lymphocyte stimulation (61). ↑ EC damage (63) Stimulated PLTs are able to secrete and store IL-1β (63). PLT ↑ neutrophil adhesion (63) levels were closely associated with plasmatic IL-1β levels (15). P-selectin • Monocytes: • In vitro: ↑ pro-inflammatory ↓neutrophil adhesion to This cytokine activates HUVECs, inducing neutrophil adhesion cytokines (65) activated EC (67) and endothelium damage (63). The co-culture of PLTs from SLE • Neutrophils: with HUVECs increased EC damage and inflammatory marker ↑ NETs formation (66) expression in an IL-1β dependent manner (64). In experimental sCD40L Plasmatic levels correlated CV • Monocytes: models of inflammation, IL-1α secreted by activated PLTs also risk and pro-inflammatory ↓TNF-α (71) played a crucial role in SI (84–86). cytokines (68, 69) ↑IL-10 (71) ↑ B cell isotype switching (70) Correlation with IDO, Treg (68) The soluble P-selectin secreted from α-granules is also TGF-β • T lymphocytes: implicated in inflammatory responses. P-selectin from activated ↓T cell function and PLTs induces the release of 3-10 folds of inflammatory cytokines proliferation (72, 73) by monocytes (65) and also promotes NETs formation (66). ↓Th1, Th17 response (72) Elevated levels of circulating soluble P-selectin may contribute ↓IFN-γ production (72, 73) to early vascular disease by promoting the adhesion of ↓granzyme B and perforin (73) leukocytes to the endothelium (87). However, soluble P-selectin ↑Treg differentiation (72) can prevent in vitro adhesion of neutrophils to activated HMGB1 • Monocytes: endothelium (67). ↑ migration and accumulation in Circulating soluble CD40L (sCD40L) is secreted mainly tissues (74, 75) by activated PLTs. In human immunodeficiency virus (HIV) ↓apoptosis (74) patients, sCD40L levels correlated with pro-inflammatory • Neutrophils: ↑ NETs formation (76, 77) cytokines (68). Moreover, PLTs support B cell isotype switching through CD40L-CD40 binding (70). In patients with an increased CV risk plasmatic sCD40L was increased and correlated with disease activity and with pro-inflammatory cytokines (69). release and the de novo synthesis of soluble factors and their The addition of thrombin-activated PLTs to TLR-stimulated binding to certain molecules on the surface of leukocytes. monocytes has been seen to reduce TNF-α and IL-6 secretion and induce IL-10 production, and were abolished by blocking Pro-inflammatory and Anti-inflammatory sCD40L (71). In HIV, sCD40L levels were correlated with IDO Soluble Factors Released by PLTs enzymatic activity and Treg frequency, in addition to induced Some of the released factors of PLTs are synthesized Treg expansion and differentiation (68). de novo, whereas others are stored and are secreted TGF-β is a potent anti-inflammatory factor, produced mainly from granules as pro-thrombotic, immunoregulatory by PLTs, which suppresses T lymphocytes function and is molecules and growth factors immediately after activation. involved in Treg differentiation. The culture of CD4+ T Molecules from dense granule components contribute to lymphocytes with PLTs enhances Th1 and Th17 cytokine hemostasis and coagulation. Molecules from α-granules production but the TGF-β secreted by PLTs activates Treg contain multiple cytokines, mitogens, pro- and anti- suppressing Th1 and Th17 response (72). PLTs inhibit CD4+ inflammatory factors and other bioactive molecules that and CD8+IFN-γ production, proliferation and granzyme B and are essential regulators in the complex microenvironment perforin expression in a TGF-β dependent manner (73). (Table 1). PLTs also release the damage-associated molecular Platelet Factor 4 (PF4, also called CXCL4) is the most pattern molecule high-mobility group box 1 (HMGB1) abundant protein secreted by activated PLTs and is deposited contributing to thrombosis process (87) promoting monocytes on endothelium. Higher levels of circulating PF4 have been migration, suppressing monocyte apoptosis via TLR4- observed in patients with chronic inflammation (78–80). PF4 ligation and the monocyte accumulation at the site of increases phagocytosis, respiratory burst, survival and the vascular thrombosis (74, 75) and promote NETs formation secretion of inflammatory cytokines in monocytes (59). PF4 (76, 77). Frontiers in Immunology | www.frontiersin.org 3 April 2021 | Volume 12 | Article 625181 Zamora et al. Platelets in Cardiovascular Risk TABLE 2 | Effects of PLT binding to other cells. binding with neutrophils (110). The increase of neutrophil- platelet aggregates in the circulation of autoimmune disease Ligands of interaction Effect on bound cells patients correlates with neutrophil activation (111) and vascular Endothelial cells GPIIB/IIIa- ICAM1 Adhesion (88) abnormalities (112) which was abolished with intravenous CD40L-CD40 Expression E-selectin immunoglobulins plus prednisolone treatment (112). However, VCAM-1 (89) even all the current evidences supports that interaction of Secretion IL-8 MCP-1 (89) PLTs with neutrophils are involved in inflammatory process Neutrophils GPIβα-Mac-1 Arrest to endothelium and vasculature damage, this interaction could have also P-selectin-PSGL-1 (90–92) NETs formation (66, 93) anti-inflammatory consequences depending on the neutrophil status. The addition of PLTs to previously stimulated TLR- Monocytes P-selectin-PSGL-1 Secretion MCP-1, IL-8, GPIβ-CD11b TNF-α, MMP9 (94, 95) neutrophils downregulates degranulation markers expression CD147-CD147 Expression TF (96) and the secretion of elastase (113). CD40L-CD40 Differentiation M1 Although monocyte-PLT aggregates are increased in macrophages (97) CVD (114), the interaction of PLTs with monocytes have Secretion IL-10 (71, 98, 99) Reduction TNF-α, IL-1β pro- or anti-inflammatory consequences depending on the (71, 99) experimental assay and the activation status of monocytes. Lymphocytes P-selectin-PSGL-1 • (SLE) B cells: As pro-inflammatory consequence, thrombin-activated PLTs P-selectin-ALCAM Upregulation CD86, through P-selectin-PSGL-1 binding induces the expression of BAFF (100) MCP-1 and IL-8 in resting monocytes (95). P-selectin expressed Secretion IL-10 (100) on the surface of PLTs induced a rapid tissue factor expression • (Psoriasis) CD4+: Secretion IL-17 (101) by monocytes (96). The binding of PLTs to monocytes through • Healthy donors: GPIβ-CD11b induces a M1 macrophage phenotype that produce Less proliferation TNF-α (97). Via CD147 axis, RA patients had more circulating (102–105) intermediate monocytes-PLTs aggregates, increasing the TNF- Less pro-inflammatory α and MMP-9 secretion (94). Autoimmune patients with a cytokines (102–105) higher CV risk have more monocyte-PLT aggregates and its associated with the activated state of monocytes (115). As anti-inflammatory consequences, it has been observed that the Binding of PLTs to Leukocytes and binding of PLTs to activated monocytes induces IL-10 production Endothelial Cells and decreases TNF-α and IL-1β production, and were abolished The interaction of PLTs with leukocytes and EC contributes by the blocking of P-selectin-PSGL-1, CD40L-CD40 axis and to SI by favoring the arrest of leukocytes on endothelium, the Ca2 + chelator (71, 98, 99). production of inflammatory cytokines and NETs formation. Although the binding of PLTs to lymphocytes has preferably Under certain circumstances, the binding of PLTs to leukocytes anti-inflammatory consequences, it was demonstrated a decreases the inflammatory response, participating in the contribution in inflammatory process. High levels of resolution of thrombo-inflammation (Table 2). lymphocytes-PLTs aggregates were observed in SLE and Under inflammatory stress, PLTs have a firm adhesion to psoriasis. In SLE, lymphocytes-PLTs aggregates had an up- endothelium via GPIIB/IIIa-ICAM-1 in a fibrinogen dependent regulation of CD86, B cell activation factor receptor and IL-10 manner (88). CD40L expressed by PLTs induces the expression production and correlated positively with plasmatic levels of of E-selectin, VCAM-1 and ICAM-1 on endothelium and the IgG, IgA, IL-10, sCD40L and renal manifestation, and correlated secretion of IL-8 and MCP-1 (89), increasing the recruitment negatively with IgM levels (100). In psoriasis, the IL-17+ CD4+ of leukocytes. had higher levels of bound PLTs and anti-TNF-α drugs normalize Although the P-selectin-PSGL-1 (P-selectin glycoprotein 1) the numbers (101), while in HIV there are more lymphocytes- axis is essential to the binding of PLTs to leukocytes, other PLTs aggregates and are associated to D-dimer levels, increasing pathways are involved in this process: P-selectin-ALCAM, the CV risk (116). GPIβα-Mac1, CD40L-CD40, P-selectin-CD15, JAM-C-Mac1, We observed that CD4+ T lymphocytes-PLT aggregates had TREM1L-TREM1, CD36-trombospondin-CD36, and CD147 a reduced proliferation and production of pro-inflammatory pathway (94, 106, 107). cytokines. A less severe phenotype and a decreased CV The interaction of PLTs with neutrophils through GPIβα- risk was observed in RA patients with higher levels of Mac-1 and P-selectin-PSGL-1 is crucial for the development circulating CD4+T lymphocytes-PLTs aggregates (102). of thrombo-inflammation and vascular damage by arresting The addition of PLTs to lymphocytes from RA synovial neutrophils to endothelium and the induction of NETs fluids decreased their proliferation and the secretion of IFN- formation (66, 90–93). The neutrophil-platelet aggregates γ, IL-17, and increased IL-10 production (103). PLTs MPs can also be seen in tissues in acute coronary syndrome cultured with Tregs prevented the differentiation into IL- and the skin of psoriatic patients (108, 109). Stimulated 17– and IFN-γ-producing cells in a P-selectin dependent TLR4 PLTs, through the binding with neutrophils, induced manner (104). The co-cultures of CD4+ CD25- T cells with robust neutrophil activation and formation of NETs (93). PLTs induced Tregs and this effect was abolished by the Induced NETs formation by PLTs was abolished blocking their blocking of glycoprotein A repetitions predominant (105). Frontiers in Immunology | www.frontiersin.org 4 April 2021 | Volume 12 | Article 625181 Zamora et al. Platelets in Cardiovascular Risk In HIV, the aberrant function of CD8+ T lymphocytes was of PLR measurements, such as EDTA dependent agglutination abolished when these cells were co-cultured with PLTs from (129, 130). HD, implying that direct contact with PLTs and TGF-β secretion contributed to this functional improvement (117). CONCLUSIONS In later stages of experimental autoimmune encephalomyelitis (EAE), there was an increase CD4+ T lymphocytes-PLTs PLTs have been considered to play a pro-inflammatory role in SI. aggregates through the interaction of P-selectin-ALCAM, However, their binding to leukocytes and EC and the secretion of down-regulating their activation, proliferation and the immunomodulatory molecules during activation also have anti- production of IFN-γ, crucial for the spontaneous resolution inflammatory consequences. Different effects were observed with of EAE. The blocking of CD4+-PLT aggregates exacerbate platelets from healthy donors or chronic inflammatory patients. EAE (118). In addition, the binding to each subpopulation of leukocytes has distinctive consequences. Further research is necessary to reveal Platelet to Lymphocyte Ratio in Systemic how platelets exert their dual function. Inflammation The platelet to lymphocyte ratio (PLR) has emerged as AUTHOR CONTRIBUTIONS a reliable marker of SI. Although elevated counts of PLTs and low counts of lymphocytes per se has been CZ and EC: literature review, manuscript preparation. SV: associated with worse prognosis of CVD, increase CV oversight, editing, and planning. All authors contributed to the mortality and morbidity and SI (119, 120), PLR predicts article and approved the submitted version. better the outcomes of CVD. The role of PLR as an independent marker in CVD and SI has been extensively FUNDING reviewed (121, 122). In patients with chronic inflammatory diseases, PLR is elevated and it correlates with markers of This study is supported by Instituto de Salud Carlos III SI (122–125). and Fondos FEDER (PI17/00072 and PI20/00184). SV was However, there are confounding factors that alter PLR. Sex supported by Fondo Investigaciones Sanitarias and a participant and ethnic origin also modulates PLR (126) as well as drugs that in the Program for Stabilization of Investigators the Direcció affect blood cell maturation in the bone marrow (127, 128). Other i d’Estrategia i Coordinació del Departament Salut de la confounding factors of PLR may be the technical limitations Generalitat de Catalunya. REFERENCES 8. Mikacenic C, Hahn WO, Price BL, Harju-Baker S, Katz R, Kain KC, et al. Biomarkers of endothelial activation are 1. Akbar N, Nanda S, Belch J, Cohen P, Khan F. An important role for associated with poor outcome in critical illness. PLoS One. (2015) A20-binding inhibitor of nuclear factor-kB-1 (ABIN1) in inflammation- 10:e141251. doi: 10.1371/journal.pone.0141251 mediated endothelial dysfunction: an in vivo study in ABIN1 (D485N) 9. Benhamou Y, Miranda S, Armengol G, Harouki N, Drouot L, Zahr N, mice. Arthritis Res Ther. (2015) 17:1–10. doi: 10.1186/s13075-015- et al. 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