Generally speaking, when the normal blood pressure is <120/80 mmHg, the blood passes normally. When the blood pressure increases, it will impact the blood vessels and cause pressure on the blood vessels (159). The long-term effect causes damage to the intima of blood vessels and the formation of red thrombosis. Damaged areas form scarring hyperplasia, which thickens the blood vessel wall and continuously forms proliferation and accumulation, narrowing the lumen and increasing the risk of thrombosis (160).

Increased immune cell infiltration may affect some mechanisms directly associated with the development of hypertension, such as promoting the release of aldosterone, increasing the reabsorption of sodium and water, and increasing circulating blood volume. T cells and macrophages produce a variety of pro-inflammatory factors when stimulated, which can lead to cardiomyocyte fibrosis, vascular dysfunction and end-organ damage. Monocytes and macrophages are particularly involved in antigen presentation to T cells and cytokine production in hypertension. Proteins modified by oxidation of highly reactive γ-ketoaldehydes accumulate in DC in multiple hypertensive mouse models. Monocyte-derived dendritic cells (MDCS) make a difference in promoting hypertension and end-organ damage by producing abundant cytokines, promoting the proliferation of CD8⁺ T cells releasing IFN-γ and IL-17A (161).

Macrophages are derived from monocytes, and in the context of vascular inflammation, monocytes are recruited to inflamed tissue and differentiate into macrophages. These macrophages then secrete pro-inflammatory mediators (IL-1), promoting vascular inflammation (162). In a review published by Philip Wenzel et al., monocytes as immune targets in the occurrence, development, and manifestation of hypertension may represent a potentially novel therapeutic avenue for treating hypertension, thereby alleviating hypertension-related end-organ damage or preventing the development or deterioration of hypertension (163). Induction of the diphtheria toxin receptor in Lysm-positive macrophages followed by low doses of diphtheria toxin-depleted bone marrow mononuclear cells reduced circulating mononuclear cells and limited ATII-induced macrophage invasion of the vascular wall. Wild-type CD11b⁺Gr-1⁺ mononuclear cells transfected into depleted LysM^iDTR mice restored Angiotensin II (Ang II)-induced vascular dysfunction and arterial hypertension (164). IL-1 is a typical mononuclear/macrophage cytokine, and activation of IL-1 receptors has been implicated in the promotion of sodium retention and elevation of blood pressure through the release of the NKKC2 sodium cotransporter (165).

Mononuclear cell infiltration, invasion, and differentiation in the heart and blood vessels are associated with the progression and severity of hypertensive diseases. In cell co-culture models, activated platelets from patients with essential hypertension are capable of releasing MCP-1, which is responsible for recruiting monocytes to sites of inflammation in blood vessels, thereby mediating the progression of atherosclerosis (166). Monocyte infiltration into the heart and blood vessels during hypertension is dependent on the CCL2-CCR2 axis, and it has been demonstrated in various studies that manipulating drugs or genes can have positive impacts on the chemokine and chemokine receptor pathway (162, 167, 168). In various rat models of hypertension induced by high-salt diet, deoxycorticosterone acetate, and human renin models, monocyte infiltration and adhesion can lead to increased blood pressure and renal injury (169–171).

In human cohort studies, the expression level of cysteine-rich intestinal protein 1 (CRIP1) in monocytes was associated with an increase in blood pressure, and this association decreased with the expression level of CRIP1 when monocytes differentiated into macrophages (172). This suggests that CRIP1 may affect the interaction between monocytes and the pathogenesis of hypertension through proinflammatory regulation and upregulation. In hypertensive patients, increased vascular stretching promotes endothelial cell activation, which enhances the conversion of monocytes into IMs and CD209-labeled monocytes, it activates STAT3 in monocytes and significantly stimulates the expression of IL-1β, IL-23, CCL4 and TNF-α in monocytes to produce these pro-hypertensive cytokines (173). In patients with poorly controlled hypertension and target organ damage (TOD) characteristics, the surface expression of NCMs costimulatory marker CD86 is higher, and the proportion of VEGF-R2 positive non-classical cells is higher, indicating that phenotypic changes in monocyte subsets are related to the progression and severity of hypertension (168).

Summarizing, in the current clinical trials and animal models related to hypertension that we mentioned, we found that organ damage resulting from hypertensive events is closely related to various immune cells of the immune system. Cells of the innate and adaptive immune systems enter target organs in the body through various routes (such as kidneys, blood vessels, myocardium, etc.) and damage target organs by releasing cytokines, matrix metalloproteinases, and ROS, ultimately leading to increased blood pressure. Several factors can activate immune cells to enter target organs, such as a high sodium diet causing an increase in sodium ions in the immune microenvironment. In addition, ECs can release both ROS and IL-6. These molecules can stimulate monocytes to become APCs, which in turn produce cytokines like IL-1β and IL-23. These cytokines can have a significant impact on T cell function. Therefore, reducing the secretion and production of cytokines by such cells in various ways contributes to improving hypertension and end-organ damage.

APS is a rare and complex systemic disease characterized by the presence of antiphospholipid (aPL) antibodies [including lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein i (anti-β2GPI) antibodies], with the main clinical features of thrombosis or pathological pregnancy (174). After antibodies bind to β2GPI protein on monocytes and ECs, the Toll-like receptor 4 (TLR-4) triggers the myeloid differentiation primary response protein 88 (MyD88) signaling pathway which leads to the activation of several protein molecules including p38 MAPK, MEK-1/ERK, and NF-κB (174–178). ECs produce microparticles (MP) and MCP-1, while monocyte adhesion to ECs increases due to the activation of the Toll-like receptor (TLR) expression. Furthermore, the presence of proinflammatory cytokines (IL-1β, IL-6, IL-8, and anti-TNF) and chemokines leads to the release of adhesion molecules including E-selectin, VCAM-1, ICAM-1, and TFs. These factors contribute to the inflammation of the blood vessels and promote the growth of ECs, which can ultimately lead to intimal hyperplasia (176, 179, 180). A study of how WB-6 (a mouse monoclonal anti-β2Gpi antibody) contacts and activates resting-state monocytes showed that monocytes internalizing WB-6 express TF and TNF-α, TNF-α stimulates ECs to express ICAM-1 and VCAM-1 (181). Later, another study identified the signaling pathways within cells involved in this process and suggested that the induction of TF expression was the result of the internalization of DNA-activated TLR9 together with cross-reactive antibodies produced by SLE secondary APS (182). It has proved that the β2GPI dimerization domain V(β2GPI-dV) dimerization of β2GPI-dV is sufficient to induce the up-regulation of procoagulant activity of monocytes (183). Antiphospholipid antibodies can activate monocytes and macrophages through systemic allergic reaction toxins (C3a, C4a) produced during complement activation (184).

Chary Lopez-Pedrera et al. first used proteomic analysis to identify changes in the proteomic pattern of monocytes directly associated with thrombotic events in APS and served as a basis for the mechanism of thrombosis in APS (185). Vera M. Ripoll performed a comprehensive proteomic analysis of human monocytes from APS patients with different manifestations using two-dimensional differential gel electrophoresis (2D DiGE). The regulation of four of these proteins showed significant differences in monocytes treated with thrombotic or obstetric APS IgG compared to those treated with healthy control IgG. The proteome of monocytes treated with thrombotic APS IgG was further described using label-free proteomics. Among the 12 most reliable proteins associated with the cytoskeleton, immune response, and coagulation function, POTEE and b-actin-like protein 3 overlapped with 2D DiGE, Abnormalities in the regulation of these proinflammatory and procoagulant proteins could serve as targets for subsequent treatment and contribute to a deeper understanding of the diversity of APS pathogenesis (186). Urine proteomics has recently been reported as a noninvasive method to distinguish primary thrombotic APS from primary obstetric APS. Urinary CXCL12 and PDGF may be potential noninvasive markers to distinguish between them, but the number of patients is small and may be biased (187).

APL can combine with β2GPI and oxLDL to produce oxLDL/β2GPI/anti-β2GPI complex, which can inhibit autophagy and increase the release of inflammatory factors in ECs through a variety of signaling pathways (such as PI3K/AKT/mTOR and eNOS signaling pathways). When a large number of inflammatory factors accumulate around ECs, monocyte-macrophages activate to release TFs, chemokines, growth factors, and metalloproteinases, and differentiate into foam cells, exacerbating atherothrombosis (177, 188, 189).

At present, it is difficult to diagnose and treat APS patients in clinical practice. Molecular analysis of monocytes in APS patients is helpful to identify unique clinical phenotypes and thus develop treatment plans. Microarray analysis of monocytes with APS revealed 547 differentially expressed genes and identified novel miRNA-mRNA-intracellular signal regulatory networks in monocytes associated with CVD. In patients with APS, the monocytes showed reduced expression of miR-19b-3p and miR-20a-5p, and those with the least miRNA expression had the highest levels of aPL (190, 191). The results of the in vitro experiments revealed that APS patients had significantly higher serum levels of HMGB1 and sRAGE, as compared to healthy individuals. anti-β2-GPI antibody induced RAGE activation and HMGB1 cell relocalization in monocytes and platelets. As an increase in proinflammatory triggers, HMGB1/sRAGE may be involved in monitoring the risk of recurrent miscarriage (192). Monocytes and ECs have a pivotal role in the development of APS, and the interaction between monocytes and ECs has been described in the previous section. Ulštok's study was the first to show a marked increase in VLA4 on monocyte surfaces in patients with APS, and in vitro stimulation of Catastrophic APS (CAPS) showed a more significant increase in VLA4, suggesting that VLA4-enhanced monocyte adhesion is involved in thrombotic pathophysiology in APS (193) (Figure 3).

Co-culture of APS monocytes with LPS increased the expression of IL-1β, IL-6, IL-23, TLR2, CCL2, and CXCL10 genes to improve the sensitivity to LPS and contribute to the formation of thrombosis, but the response was weak in healthy donor cells (194). Reduced levels of ATP result in decreased inflammation among APS monocytes by blocking unidentified signals stimulated by LPS and inhibiting ATP-mediated production of IL-1 through the inflammasome and IL-10 (194, 195). Immunomodulation of plasma exchange reversed the expression of IL-1 β, IL-6, IL-23, CCL2, P2X7, and TNF-α in APS monocytes, with mRNA expression levels returning to the normal range (196). For secondary thromboembolism in APS, it is generally accepted that direct oral anticoagulants can prevent this from occurring. There are currently many anticoagulant drugs of choice in clinical practice, such as DOAC rivaroxaban and warfarin drugs. Compared with warfarin, DOAC rivaroxaban not only provides anticoagulation but also reduces the frequency of bleeding events and does not require patient diet control (197).

Atherosclerosis is a slowly progressing condition of the large and medium-sized arteries, characterized by the gradual build-up of plaques over time. Thrombotic complications of atherosclerotic diseases, such as ACS, occur suddenly and often without warning signs. The long-term process of atherosclerotic plaque initiation and formation is thought to be accelerated by different risk factors, including traditional factors such as smoking, hypertension as mentioned above, hyperglycemia, and severe hyperlipidemia (198). It is increasingly believed that environmental factors, such as air pollution, noise, sleep disorders and stress, contribute to atherosclerotic events in part through the activation of inflammatory pathways (199). The inflammatory mechanisms run through the whole process of atherosclerosis formation, and mononuclear macrophages play a key role. In early atherosclerosis, LDL remains in the intima of blood vessels, mediated by oxidase, lipolysis, proteolytic enzymes, and ROS (200). A variety of danger-associated molecular patterns (DAMP) are modified to obtain immunogenicity. Immunogenic LDL activates vascular ECs and mobilizes immune cells (mainly monocytes and T cells) to inflammatory tissues, mediated by locally produced chemokines, as previously described in the context of arterial thrombosis. Chemokines (CCR2, CCR5, and CX3CR1) bind to receptors on monocytes to promote migration to tissues. When three chemokine receptors, CCR2, CCR5 and CX3CR1 were blocked, atherosclerosis in hypercholesterolemic mice was virtually eliminated by inhibiting the aggregation of monocytes into inflammatory tissue (201). This suggests that all monocyte subsets are involved in the formation of atherosclerosis.

The atherosclerotic process may be a training immune process (Figure 3). Studies have shown that monocytes, as innate immune cells, can form features of immune memory after brief exposure to microorganisms (202). Unlike the specific memory of adaptive immune cells, trained immunity is characterized by its nonspecificity and ability to induce a long-lasting proinflammatory phenotype in monocytes/macrophages through epigenetic reprogramming, particularly at the level of histone methylation (202). In addition, non-microbial endogenous stimuli can also induce trained immunity, and current studies include lipoproteins and adrenal hormones, hyperglycemia, and other factors that contribute to the development of atherosclerotic cardiovascular disease (ASCVD) (203, 204). Monocytes immunized by Ox-LDL training are induced through the Akt-mTOR-HIF-1α pathway, and intracellular metabolic glycolysis and oxidative phosphorylation are up-regulated, which is an important pathway to promote proinflammatory cytokines (205–207). Pharmacological inhibition of the mTOR pathway and related signaling molecules, as well as inhibition of 2-deoxyglucose glycolysis, prevents glycolysis, ROS formation, and proinflammatory initiation in monocytes/macrophages (206, 207). A recent study in 243 healthy volunteers showed that oxLDL-induced training immunity led to changes in the balance of steroid hormones within monocytes. Progesterone inhibits oxLDL-induced training immunity through ribocorticosteroid receptors and minerocorticoid receptors, an effect that may help reduce CVD risk in premenopausal women (208).

In addition to the promotion of cytokine proliferation, macrophages induced by Ox-LDL showed high expression of Ox-LDL recognition receptors CD36 and SR-A and low expression of anticholesterol receptors ABCAI and ABCG1, thus enabling macrophages to have a stronger lipid absorption capacity (209). These processes accelerate the formation of atherosclerosis. Differentiated macrophages, as key cells in atherosclerosis, are transformed into foam cells, and subsequent increase in cholesterol load over time causes the triggering of unfolded protein responses in the ER, from intracellular crystallization to precipitation and activation of inflammasomes, ultimately leading to programmed cell death (210). Foam cells accumulate to form an atherosclerotic core. The properties of lipid material, cholesterol crystallization, accumulation of foam cell fragments to form an atherosclerotic core, and ensuing thinning of the fibrous cap result in a high degree of thrombosis (211, 212). Interestingly, the investigators discovered that neovascularization was prevalent in atherosclerotic plaques, and highly neovascularized plaques were more susceptible to rupturing than their stable counterparts. Matrix metalloproteinases secreted by monocytes/macrophages were responsible for this phenomenon by deteriorating and redesigning the ECM and activating or disintegrating growth factors. As a result, stable atherosclerotic lesions may become unsteady high-risk plaques due to intraplaque hemorrhage.

Macrophages were thought to be major players in the formation of atherosclerosis as well as thrombotic complications. Although the connection between atherosclerosis and immunity in humans is constantly evolving, some of our understanding of this relationship comes from research conducted on animal models of CVD. However, due to inherent biological, genomic, and environmental differences, the results obtained therein cannot be fully transferable to the human environment. Potential therapeutic approaches against atherosclerosis include targeting monocytes/macrophages recruitment, polarization, cytokine profiling, ECM remodeling, cholesterol metabolism, oxidative stress, inflammatory activity, and non-coding RNA. Besides, folic acid can restore hyperlipidemia (HL) and hyperhomocysteinemia (HHcy)-mediated aberrant DNA methylation and decreased ARID5B expression, thereby inhibiting atherosclerotic plaque formation by reducing the proportion of intermediate monocytes (213).

In recent years, there has been significant interest in understanding the role of monocytes and monocyte-derived extracellular vesicles (MDEVs) in the major risk factors for atherosclerosis (214, 215). Several studies have reported a significant association between monocytes and obesity, a major risk factor for atherosclerosis (216, 217). These studies have shown that obesity leads to increased levels of chemokines and cytokines, promoting monocyte recruitment and activation. It also results in increased oxidative stress and inflammation, leading to MDEV release (218). MDEVs have been shown to exert pathogenic effects by promoting endothelial dysfunction and a pro-inflammatory state, exacerbating atherosclerosis (219). In addition, in a clinical trial of obese women without other cardiovascular risk factors, the researchers found that circulating procoagulant microparticles were increased in obese patients compared with healthy controls, and obese patients had an increased risk of thrombosis, suggesting that obesity as a major risk factor for atherosclerosis is associated with the release of MDEVs (220).

Diabetes is another major risk factor for atherosclerosis, with chronic hyperglycemia leading to increased oxidative stress and inflammation (221). High glucose levels induce monocyte activation, leading to MDEV release, and increased endothelial adhesion molecules, resulting in a pro-inflammatory and pro-thrombotic environment (222). The concentration of MDEVs in plasma of patients with type 2 diabetes was much higher than that of healthy individuals, and the amount of MDEVs was positively correlated with platelet activation markers (223, 224). Furthermore, MDEVs have been shown to induce endothelial dysfunction and increase monocyte and macrophage recruitment, aggravating atherosclerosis in diabetes (219).

Hypertension is another major risk factor for atherosclerosis, and monocytes are involved in its pathogenesis. A study showed that shear stress induces monocyte recruitment, activation and migration, promoting inflammation and neointimal formation (225). MDEVs have also been implicated in hypertension. In a clinical trial of 359 hypertensive patients, investigators observed increases in MDEVs and sVCAM-1 regardless of their presence or absence of diabetes (226). In another study, the expression of MDEVs and platelet activation markers (CD62P, CD63, PAC-1, and annexin V) was much higher in hypertensive patients than in healthy individuals, suggesting that hypertensive patients are more prone to atherosclerosis (227).

Hypercholesterolemia is also a cause of atherosclerosis. In response to high levels of cholesterol, monocytes can infiltrate the arterial wall and differentiate into macrophages, which can take up and accumulate lipids, leading to the formation of foam cells and ultimately the development of atherosclerotic plaques (228). Although the exact mechanism is not yet fully understood, recent studies suggest that MDEVs may also be involved in the development of atherosclerosis, and secretion of MDEVs by monocytes can activate endothelial cells and other immune cells and promote inflammation and further atherosclerotic plaque formation (229). Clinical trials have found that elevated oxidized LDL cholesterol in hypercholesterolemia induces increased release of MDEVs (230). MDEVs appear to be markers for the diagnosis of atherosclerotic plaques in patients with hypercholesterolemia, and the number of circulating microparticles before thrombosis can indicate atherosclerotic plaques in the subclinical stage of patients with hypercholesterolemia (231–233).

Other risk factors for atherosclerosis, such as smoking, aging, and dyslipidemia, have been associated with monocyte activation and MDEV release. Smoking induces oxidative stress and inflammation, leading to increased monocyte activation, and MDEV release (234). In cell experiments simulating smoking environments, tobacco smoke-exposed monocytes/macrophages have been found to induce biologically active procoagulant MDEVs in cells, which may be associated with activation of JNK, p38, ERK, and MAPK (235). Aging is a primary risk factor for atherosclerosis, characterized by declines in tissue and cell functions resulting in increased inflammation and oxidative stress, leading to MDEV release (236). Dyslipidemia, characterized by increased levels of LDL cholesterol, induces monocyte activation and lipid accumulation in macrophages, leading to foam cell formation and atherosclerosis (237). In addition, IL-33 acts as a pro-inflammatory factor, induces TF expression in monocytes, releases procoagulant MDEVs, and ultimately forms a prothrombotic state of atherosclerosis (238).

In summary, monocytes and monocyte-derived extracellular vesicles play a crucial role in the pathogenesis of atherosclerosis, and different major risk factors for the disease have been associated with their activation and release (239). Obesity, diabetes, hypertension, smoking, aging, and dyslipidemia all promote monocyte activation and MDEV release, leading to increased inflammation, oxidative stress, and endothelial dysfunction, culminating in atherosclerosis. A better understanding of the role of monocytes and MDEVs in atherosclerosis could lead to novel therapeutic interventions targeting their recruitment and activation, potentially preventing or slowing the progression of this debilitating disease.

RHD is a condition caused by damage to the heart valves from rheumatic fever (RF), which is an autoimmune response to untreated streptococcal throat infections (240). Left atrial (LA) thrombosis is a common complication with RHD and mitral stenosis (MS) (241). As early as 1991, the luminol-enhanced chemiluminescence technique was used to study the production of oxygen free radicals (OFR) by monocytes and neutrophils in the peripheral blood of patients with RF and RHD (242). It has been observed that in RHD patients, phagocytes are capable of penetrating the myocardium and possibly contributing to the development of cardiac injury by generating OFR (242). In a clinical study of mitral valve resection in patients with rheumatic MS, histological studies have revealed a positive correlation between the degree of infiltration of inflammatory cells in valve tissue and the levels of MMP-1 and IFN-γ. In addition, in an in vitro cell assay, IFN-γ was found to increase MMP-1 expression in monocytes (243). The risk of embolus dislodging and causing thromboembolism may increase due to the easy tearing of valve tissue resulting from the thickening of collagen and structural abnormalities in the valve tissue caused by inflammatory cell infiltration.

The expression of inflammatory cells and inflammatory genes in the aortic valve of female RHD patients was significantly higher than that of male patients. More monocytes and macrophages infiltrate into the aortic valve to produce IFNγ and IL8, which as major Th1 cytokines, participate in the positive feedback between macrophages and Th1 cells to accelerate the secretion of pro-inflammatory cytokines. The NFKB pathway plays a crucial role in enhancing the autoimmune response of the aortic valve in female RHD patients by increasing mononuclear/macrophage infiltration and pro-inflammatory cytokine (especially Th1 cytokine) levels. Upon activation, phosphorylated p65 enters the nucleus and triggers the transcription of inflammatory genes, which further exacerbates the inflammation of the damaged aortic valve (244).

RF is a complex inflammatory autoimmune disease that involves the interaction of multiple pro-inflammatory agents produced by activated neutrophils and macrophages, resulting in a synergistic pathological effect (245). In individuals with rheumatic mitral stenosis and atrial fibrillation, pro-inflammatory M1 macrophages are primarily observed in the atria of those with mitral stenosis, atrial fibrillation, and thrombosis. The inflammatory effect of M1 cells may be related to the up-regulation of eNOS expression. In addition, the polarization of M1 macrophages towards M2 is inhibited due to the down-regulation of M-CSF (246).

DVT is a kind of thrombotic disease. It refers to venous reflux disorders caused by abnormal coagulation of blood in deep veins (247). It often occurs in the lower limbs. It is a common and serious complication of hospitalized patients, especially those after major surgery and long-term bedridden patients, with high incidence and serious consequences. Detachment of the thrombus can cause PE, and both are collectively referred to as VTE.

The mononuclear/macrophage system is essential in both the formation and resolution of DVT. In mice with venous thrombosis, inflammatory bodies are activated, triggering venous thrombosis through pyrodeath and TFs released by inflammatory monocytes and macrophages (248). Lack of caspase-1 but not caspase-11 protects mice from venous thrombosis. The monocyte signaling pathway, key enzymes and thrombolytic regulators regulate the occurrence of DVT, which can be used as a molecular target network to study the treatment of DVT. Protein tyrosine kinases participate in the activation of monocytes and ECs. For example, tyrosine kinase PYK2 regulates platelet activity and TF expression by stimulating monocytes and ECs, and is involved in the regulation of natural immunity and inflammation (249). In a mouse experiment, the number of inflammatory Ly6^Chi monocytes controls DVT formation, growth, and regression, and Nur77 agonist may be an ideal candidate for therapeutic intervention with inflammatory monocyte activity in patients with DVT to prevent thrombosis growth and accelerate regression (250). Inhibit the formation of Tbet⁺ interleukin-12 from bone marrow monocytes and accelerate thrombus regression (251). Modulating inflammatory immune responses may be a way to improve DVT treatment. The effects of MMP-9 on the loss of compliance during thrombolysis and the biomechanics of vein walls contribute to the development of specific molecular therapies for DVT. With the age of thrombosis, IFN-γ is mainly infiltrated by macrophages, and IFN-γ/STAT1 signaling pathway is activated to negatively regulate the expression of Mmp-9 and Vegf genes in PMA-induced macrophages (252). The use of anti-IFN-γ monoclonal antibody can accelerate the resolution of DVT. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) not only mobilized monocyte lineage cells into peripheral blood but also induced higher expression of CCR2 protein, thus enhancing the regression and recalculation of venous thrombosis (253). Circulating monocytes and monocyte-derived macrophages in patients with idiopathic DVT exhibit significantly increased M1 polarization, which can significantly up-regulate the expression of endothelial cell adhesion molecules (134). The thrombus targeting adenovirus uPA (ad-uPA) gene transduction of human blood monocyte-derived macrophages (HBMMs) increases their fibrinolytic activity. In an experimental model of venous thrombosis, systematic administration of uPA up-regulated HBMMs reduced the size of the thrombus (254). Alternatives to delivering fibrinolytic agents are worth exploring. Loss of prostag-landin-endoperoxide synthase (PTGS) alters the natural distribution of ANXA2 in mononuclear/macrophages, increases TF expression and activity, and leads to venous thrombosis. Targeting PTGI2/ANX2/TF pathways, such as treatment with cabpaprost, inhibits nuclear ANXA2 transport, controls monocyte TF activity, and prevents the occurrence of DVT (255).

DN has emerged as a pervasive renal disease, causing end-stage renal failure on a global scale (256). As one of the most serious and harmful chronic complications caused by diabetes, DN is one of the manifestations of diabetic systemic microangiopathy (257). DN has a prethrombotic state and obvious endothelial dysfunction (258). With the increase of urinary protein and the progression of the disease, it is easy to appear hypercoagulation, and then thrombosis.

Inflammatory cell infiltration is a consistent feature of the early stages of DN, particularly the influx of mononuclear cells into the affected tissues and the infiltration of macrophages into the kidney (259, 260). This influx is thought to be due to the activation of innate immunity accompanied by the development of a chronic low-grade inflammatory response, but may also be related to differences in monocyte phenotype and function. Experiments showed that diabetes increased the number of monocytes and had no effect on the total number of white blood cells. At the same time, the number of CD14⁺CD16⁺⁺ NCMs was significantly reduced by diabetic status, but only in patients with diabetic complications (261). The circulating monocytes phenotype can be changed by diabetic complication status. Changes in monocyte activation and function have also been reported in inflammatory pathways in diabetes, such as increased monocyte adhesion to ECs and enhanced TLR signaling pathway conduction in monocytes (262). Mouse data showed that monocyte CD163 and sCD163 changes predate DN. CD163+ monocytes with a high circulating proportion have anti-inflammatory effects and may protect against diabetes complications (263).

Macrophage infiltration and activation are evident in the renal biopsies of diabetic animal models and patients with DN (264–266). Therefore, monocytes need to be activated and migrate from the circulation to differentiate and infiltrate the renal mesangium. Under the influence of high glucose, monocyte adhesion, migration, differentiation and MMP expression can be enhanced by increasing the secretion of pro-inflammatory cytokines in mesangial cells, and thus MMPs can mediate the degradation of ECM (260, 267). Mesangial cell-monocyte interactions are important to activate monocyte migration from circulation to the kidney in early DN. The pro-inflammatory cytokines TNF-α and IL-6 can induce the expression and adhesion of MMP-9 in monocytes (260). Moreover, the interaction between monocytes and human renal mesangial cells (HRMCs) is also through MMP-2 and fractalkine. In the Monocyte-HRMC co-culture system, AGEs not only directly down-regulated MMP-2, but also indirectly down-regulated the expression and activity of MMP-2 through up-regulated fractalkine, thus increasing the expression of fractalkine, which is mainly used as chemotactic agent (268) (Figure 3). The presence of such crosstalk between monocytes and HRMCs has been interpreted to be related to abnormal deposition of ECM and migration of monocytes into tissues.

Diabetes can induce renal MCP-1 production, and serum and urinary MCP1 levels are elevated in early DN, which can be used as markers and possible mediators of early DN, as well as to evaluate renal inflammation in diabetic patients (269, 270). Increased expression of MCP-1/CCL2 in the kidney is considered a crucial contributor to the initiation of monocyte recruitment in the tubulointerstitium (271, 272). Exposure to MCP-1 and high-glucose environments induces infiltration and activation of macrophages, resulting in the release of ROS, profibrotic growth factor (TGF-β, PDGF) and pro-inflammatory cytokines (IL-1, TNF-α, MCP-1) (272–274). The amplified inflammatory response mediates parenchymal cell injury and death leading to decreased renal function, and myofibroblast proliferation promotes renal fibrosis. These tandem processes together promote the progression of DN, lead to the development of kidney failure and cause vascular dysfunction. Inhibition of MCP-1 in DN shows strong therapeutic potential by reducing persistent proteinuria. Spiegelmer® emapticap pegol (NOX-E36) continued to restore glomerular endothelial glycocalyx and barrier function, decreased CCR2-expressing Ly6^Chi monocytes in peripheral blood, and polarization of tissue macrophages toward anti-inflammatory phenotypes (275). Activation of the renin-angiotensin system (RAS) is a characteristic manifestation of DN (276).

Activation of RAS is pro-inflammatory, and pro-fibrotic and enhances oxidative stress. By increasing the production of MCP-1 and osteopontin in renal tubule cells, it facilitates the adhesion of monocytes to renal ECs and thus their entry into the kidney. Under the activation of various proinflammatory cytokines and RAS, macrophages differentiate into M1 proinflammatory phenotypes, leading to the development of DN. Under the antagonistic drugs of RAS, the phenotypic transformation of macrophages and the number of infiltrates can be improved, thus reducing proteinuria and correcting renal disorders (277, 278). Furthermore, recent studies have shown that signal communication between macrophages and renal tubular epithelial cells (TECs) can be used as targets in the treatment of DN. For example, the exosome/miR19b-3p/SOCS1 axis mediates the communication between injured TECs and macrophages, leading to the activation of M1 macrophages (279). During DN progression, IRG1 enrichment, lipotoxic tec derived EVe activates macrophages through TGFβR1-dependent pathways and subsequently up-regulates the expression of many inflammatory genes, thereby inducing inflammation and damage in DN. Meanwhile, the LRG1/TGFβR1 signaling pathway can also increase the expression of TRAIL in macrophages, and the macrophage-derived EVs enriched with TRAIL can promote the apoptosis of TECs, acting as a feedback loop in DN (280). Proteinuria induces glycolysis in renal macrophages by stabilizing HIF-1α through tubular epithelial-derived EVs (281). These targets may be some important links to subsequent regulation, which needs further in-depth study.

Indicators related to monocytes can be an important predictor of DN, and increased Monocyte-lymphocyte ratio (MLR) is significantly associated with the risk of DN (282). Higher monocyte to high-density lipoprotein cholesterol ratio (MHR) levels for patients with DN compared to others (283).