The inflammasomes are cytosolic protein complexes, such as NLR-family pyrin domain-containing protein (NLRP)1 and NLRP3 mainly expressed in innate immune cells (like monocytes and macrophages) and endothelial cells, that identify pathogens and activate inflammatory responses, including the intracellular IIS receptors (52, 53). As inflammasomes are major components of the IIS, they mediate important inflammatory responses and pyroptosis, which are tightly associated with endothelial dysfunction. Improperly activated inflammasomes are involved in the potential pathogenesis of many inflammations related diseases (54). NLRP3 is the most characteristic inflammasome among the pattern recognition receptors (PRRs) that recognize damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) to initiate and promote an inflammation response (55). Briefly, a wide range of DAMPs or PAMPs stimulate NLRP3 activation by inducing ion transporting (e.g., K⁺ efflux and Ca²⁺ influx) and lysosomal leakage. The activated NLRP3 inflammasome then triggers caspases to induce cleavage of inactive proinflammatory cytokine precursors, such as pro-IL-1β, pro-IL-18, and pro-IL-37 ( Figure 1 ) (48). Numerous studies show that activated NLRP3 inflammasomes are tightly associated with many chronic inflammatory and metabolic diseases, such as ischemic heart diseases and diabetes mellitus, stroke, atherosclerosis, and hypertension (56–59). Studies have suggested that inflammasomes and their related cytokines are tightly associated with raised blood pressure. According to Dalekos et al., an elevated serum concentration of IL-1β was detected in patients with hypertension (60). Endothelial cells are not only the action target of IL-1β but also produce IL-1β (61). In vitro experiments show that monocytes derived from hypertensive patients can release a high level of IL-1β in response to the stimulation of Ang II or lipopolysaccharide (LPS) (62). In addition, the production of mitochondrial ROS is a vital component of cellular oxidative stress, and NLRP3 activation is indispensable in this process. More and more agonists have been reported to produce vascular inflammation and injury by triggering NLRP3 inflammasome activation. According to Xie et al., the NLRP3 inflammasome is involved in visfatin-mediated vascular injury, which may cause atherosclerosis (63). IL-1β and IL-18 would then be released into the blood flow to activate more inflammatory cells and thereby expand the inflammatory response when inflammasomes are activated.

Recent research suggests that endothelial dysfunction is associated with activated NLRP3 inflammasomes through the release of HMGB1. Activated NLRP3 inflammasome and subsequent release of HMGB1 have been considered as the underlying cause of cell-to-cell junction breaks in mouse vascular endothelial cells treated with high-glucose levels (64). Interestingly, NLRP3 deficiency has a significantly protective role via preventing tight junction disruption in diabetic mice and ameliorating endothelial permeability in endothelial cells in vitro (64), and inhibiting the NLRP3 inflammasome by pharmacological inhibition also produced potent therapeutic effects (65). More recently, knockdown of NLRP3 also exhibited remarkable effect on lowering blood pressure, improving vascular remodeling and insulin resistance, and ameliorating or delaying the atherosclerosis via regulating metabolism, relieving oxidative stress and reducing release of inflammatory cytokines (58, 66, 67). WEHD, a caspase-1 inhibitor, could significantly reduce inflammasome activity and prohibited ATP-induced hypertension in mice (68).

Traditionally, essential hypertension was thought to be caused by hemodynamic changes, but in recent years, numerous studies have revealed that inflammatory cytokines play a significant part in promoting the progression of hypertension via affecting vascular and renal function. Cytokines are a major component of the immune system and the main performer of inflammatory response, which connects them with vascular remodeling and hypertension. Until recently, the connection between how inflammation and immunity affect blood pressure levels was not well understood. According to previous observations, numerous T cells and monocytes/macrophages accumulated in vessels and kidneys in the mice model with renal ischemia-reperfusion injury (69). Based on other’s and our own research, these cells have been shown to secret potent cytokines that impair organs, especially the heart and kidneys. Modern experimental technologies have demonstrated that a variety of cytokines are involved in the initiation and progression of hypertension ( Table 1 ).

Recently, we have gained greater understanding of the role of gut microbiota and neuroinflammation in the pathogenesis of hypertension. Interaction between the gut microbiota and epithelial cells of the gut-brain axis is involved in regulating ANS activity to control blood pressure. The endocrine pathway of hypertension mainly involves the activation of the hypothalamus-pituitary-adrenal axis. The complex interactions of immune-regulatory organs such as bone marrow, gut, and spleen, which can enhance vascular tone and contraction, can contribute to increases in peripheral resistance and blood pressure.

In addition, increased neural activity may result in neuroinflammatory events, activating microglia, producing more proinflammatory molecules, and an inflammatory environment in autonomic brain regions. Disorder of the gut-brain axis, including gut microbiota dysbiosis, gut epithelial injury, and deranged brain input, is responsible for hypertension through inflammatory mediators, metabolites, circulating bacteria, and altered afferent information, causing neuroinflammation and disorder of the ANS. This in turn can negatively impact gut functions and associated microflora to create a vicious spiral. In this section, we address the role of an impaired gut-brain axis in the pathophysiology of hypertension.

The ANS can regulate the arterial blood pressure by controlling the vasomotor activity of sympathetic and parasympathetic nerves. Numerous inflammatory cytokines, including IL-1β (105), TNF-α, IL-6 (88), and IFN-γ (91), were detected in animal brains in hypertension models, and these cytokines have been demonstrated to raise blood pressure by increasing sympathetic nerve activity. Furthermore, the impaired blood-brain barrier is another important cause of neuroinflammation. For example, increasing evidence suggests that Ang-II as well as gut microbes and their metabolites affect the blood-brain barrier permeability, which allows more cytokines to enter the brain. Once the blood-brain barrier is disturbed, circulating inflammatory factors and toxins can enter autonomic brain regions, interfering with normal neural activity and causing hypertension (106). Microglial cells are the important part of the IIS in the brain, and responsible for homeostasis of the central nervous system via clearing senescent and apoptotic cells (107). Inhibition of microglia activation helps to decrease hypertension and alleviate sympathetic activation and peripheral inflammation (108). Interestingly, specific deletion of microglia could significantly relieve the Ang II-induced elevation of blood pressure and inflammation (109).

In recent years, the gut microbiota has become a hot research topic in CVDs and metabolic diseases and is considered as the most promising interventive target of chronic diseases in the coming decades. Rapid developments and major breakthroughs in sequencing technologies have helped recognize the important role of the gut microbiota on body homeostasis, especially regarding obesity, insulin resistance, and CVDs. Animal and human experiments consistently showed that patients with hypertension had significantly lower gut flora richness compared with that of normotensive subjects (110). Two concurrent studies have reported the relationship between gut microbiome composition and hypertension (111, 112). A recent study by Mell et al. highlighted differences in the cecal microflora between salt-sensitive and -tolerant strains in Dahl rats (111). Moreover, changes in the variety and abundance of several short chain fatty acids in the plasma were observed after cecal transplantation. Thus, there is reason to believe microbial composition may affect the levels of short chain fatty acids in the plasma via roles in metabolism. Significant dysbiosis due to decreased microbial richness, diversity, homogeneity, and increased Firmicutes/Bacteroides ratios in hypertensive animals have been observed by comparing changes in the fecal microflora in spontaneously hypertensive and chronic Ang II-infused hypertensive rats (112). Another difference between the microbiota of normotensive and hypertensive patients is the production of LPS. Veillonellae are enriched in gut microbes in human hypertensive patients and produce LPS. Biofilms encapsulate bacterial communities in an extracellular matrix produced by bacteria, increasing their adhesion, and creating an environment that is more suitable for their grow. LPS-producing bacteria in biofilms were more inflammatory than Gram-negative bacteria were without biofilm protection (113, 114). This shows that the hypertensive microbiota are more inflammatory throughout the body and, because of the arrival of LPS in the brain, are more responsible for the possibility of ANS activation and hypertension.

Innate immunity is the rapid, nonspecific defense response to a variety of exogenous stimuli that is often considered as the early stage of inflammation. The key effectors are mainly monocytes, M1 macrophages, natural killer cells, and neutrophils. Monocytes/macrophages have been revealed to be tightly associated with the microvascular remodeling. In a rodent model with a deficiency in macrophage colony stimulating factor, Ang II failed to induce endothelial injury and vascular oxidative stress or elevate blood pressure (115). Consistently, removing lysozyme M-positive myelomonocytic cells prevented mice from suffering severe hypertension (116). As mentioned above, macrophages are crucial to the progress of hypertension and, although the exact mechanisms remain elusive, increasing evidence indicates that a large amount of ROS derived from activated macrophages may cause irreversible vascular endothelial cell damage and microvascular remodeling, causing increased peripheral arteriolar resistance (116, 117). Experiments have shown that activated monocytes can produce endothelial dysfunction. Chemokines become involved in the pathological process of hypertension by recruiting immune cells to the site of endothelial injury, causing further impairment of endothelial function. An increase in the number of monocytes and neutrophils with the CXCL1 receptor CCR2 can be clearly detected in patients with hypertension, suggesting that blocking CCR2 may alleviate inflammation and control blood pressure. Neutrophils are an important component of the IIS and produce large quantities of cytokines and superoxide anion when stimulated (118). Ang-II could connect thromboinflammation with essential hypertension by inducing neutrophil to release extracellular traps. The use of plasma from untreated patients with hypertension to stimulate neutrophils in normal patients can facilitate the production of endothelial collagen, thereby causing vascular remodeling and injury (119). More recently, the gene SH2B3 (LNK) that encodes SH2B adaptor protein 3 have been confirmed that regulate the immune cell (notably T cells and macrophages) development, differentiation, and signaling in the hypertension according to the genome-wide association studies (120). Therefore, elucidating molecular mechanisms where SH2B3 regulating immune cells in hypertension may found novel therapeutic targets for hypertension.

Increasing evidence suggests that the activated AIS promotes the pathogenesis of hypertension and aggravates targeted organ damage. The AIS executes a highly specific response and is regulated by activated T and B lymphocytes. According to specific markers on the cells, T lymphocytes are divided into two subpopulations: CD4⁺ and CD8⁺ T lymphocytes. Although it has been confirmed that both types of T cells are involved in the initiation and progression of hypertension, results based on in vivo models showed that CD4⁺ T cells are likely to the key factor in promoting hypertension (121). However, Trott et al. reported that CD8⁺ T cells can be a crucial motivating force in experimental hypertension. Once the endogenous or exogenous antigens presented by antigen-presenting cells are recognized, lymphocytes are activated and differentiated into T effector cells or Treg cells (122). Under the action of inflammatory cytokines or chemokines, these activated T lymphocytes target the site of inflammation. The balance among T cell subsets can influence inflammatory responses. Kassan et al. (123) described the relationship between Tregs and vascular dysfunction in patients with hypertension and found that endothelial damage, plaque rupture, and arterial occlusion mainly resulted from the imbalance of Treg cells.

The hypothesis that T lymphocytes are the important participant in the pathogenesis of hypertension was proposed many years ago but failed to receive enough attention initially. It was not until the past 20 years that experimental evidence confirmed the exact role of T lymphocytes in elevating blood pressure and promoting vascular injury (76). Elevated blood pressure may further activate the immune response via modifying self-antigens or generating new antigens. Studies have shown that several T lymphocyte subsets may promote the occurrence of hypertension and vascular remodeling (124). T- and B-lymphocyte-deficient mice, produced by silencing recombination-activated gene 1 (RAG1^−/−), exhibited a blunted hypertensive response compared with that in control mice in the Ang II-induced hypertension animal model. Adoptive transfer of effector T cells, but not B cells, to the RAG1^−/− mice restored the effects of Ang II (76). Moreover, in mice lacking T cells, there was insufficient infiltration of innate immune cells in vascular pathological sections, which was possibly related to the absence of cytokines derived from Th cells (76).

Studies have demonstrated that T lymphocyte-mediated immune responses can be induced by oxidative stress. The role of Th17, an important part of effector T cells, in hypertension has been identified by Madhur et al. (125). Th17 not only promotes but can also inhibit inflammation. Using the Ang II-induced hypertension animal model, improved vascular function, lowered oxidative stress levels, and decreased T lymphocyte infiltration have been observed in IL-17^−/− mice compared with these parameters in control mice (125). Madhur et al. revealed that the blood pressure level is positively correlated with the amount of circulating Th17 cells and that the inhibition of IL-17 contributes to the improvement of hypertension, which is consistent with previous research. In addition, enhanced acquired immunity due to genetic susceptibility, and vascular inflammation due to decreased Treg immunosuppressive function may contribute to hypertension (126). Viel et al. proposed a famous hypothesis that the genetic predisposition based on loci on chromosome 2 where many proinflammatory genes locate enhances adaptive immunity (127).

As mentioned above, chronic inflammation has a close association with elevated blood pressure. Clinical studies indicate that elevated CRP levels at baseline are more likely due to an increased risk of hypertension (138). Although inflammatory activation is closely associated with elevated blood pressure, so far there is no obvious data supporting that routine use of anti-inflammatory drugs can treat hypertension. Table 2 describes several drugs that may lower blood pressure via an anti-inflammatory effect. A preliminary analysis of one clinical study shows that minocycline, a broad-spectrum tetracycline antibiotic has a continuous antihypertensive effect in patients with hypertension (139). Mycophenolate mofetil is a well-known immunosuppressant, whose active metabolite inhibits the activation and synthesis of T and B lymphocytes by inhibiting dihydrolactate dehydrogenase and thereby decreases the synthesis of pyrimidine nucleotides, which can significantly lower blood pressure in salt-sensitive hypertension (140). In addition, a significant effect of mycophenolate mofetil on lowering blood pressure has been observed in patients suffering from psoriasis and rheumatoid arthritis (141). Another observational study showed that long-term use of immunosuppressive drugs can alleviate arterial stiffness and lower blood pressure in patients with chronic kidney disease (142). A monoclonal antibody against IL-17A could lower baseline blood pressure in patients with psoriasis (143). In addition, an IL-1 receptor antagonist (anakinra) could significantly reduce the blood pressure after a 14-day treatment via specifically inhibiting the actions of IL-1α and IL-1β (145, 146), but no significant antihypertensive effect was observed with canakinumab (an IL-1β antagonist) in large-scale randomized controlled trials in patients with previous myocardial infarction and elevated hsCRP (147). The study suggests that the mechanisms of reducing major adverse cardiovascular events are not associated with the change of blood pressure. The main reason that canakinumab does not lower the blood pressure may be related to the enrolled populations of whom 80% are patients with hypertension and were taking antihypertensive drugs, which may mask the real antihypertensive effect of canakinumab. Statins are widely used lipid-controlling drugs in clinics and can significantly reduce cholesterol levels, thereby reducing the risk of CVDs and improving prognosis. Statins also show multiple effects and have particular benefits on the cardiovascular system. Mounting evidence has demonstrated that statins have mild antihypertensive effects, especially in patients with intractable blood pressure and with hypertensive target organ damage (102, 144). The underlying mechanism whereby statins reduce blood pressure may be associated with the protective effect on the vascular endothelium by inhibiting the production of ROS, reducing the circulating level of proinflammatory cytokines, and inhibiting the expression of adhesion molecules on vascular endothelial cells and smooth muscle cells.

Antioxidants are substances that effectively trap ROS, so they can reduce oxidative damage and may lower blood pressure ( Table 3 ). The use of antioxidants, such as vitamin C and E, have been confirmed as effective therapeutic strategies in lowering the level of blood pressure. Vitamin C as an enzyme manager, increases eNOS activity and reduces ROS, and has been proved to improve vasodilation in hypertensive patients (158). Studies from humans and animals have shown that vitamin C can enhance endothelial function in a variety of situations (159). The effect of antioxidants on lowering blood pressure and enhancing vascular function has been confirmed in the hypertensive animals (160). One possible reason is that the free contractile response to norepinephrine is increased in patients with hypertension, which can be reduced by vitamin C (148). However, in several large-scale clinical trials, the effect of supplementation of vitamin C on blood pressure was unpredictable and more experiments are needed to confirm the exact effect (161–163), which may result from the reduced bioavailability of NO. B-cell lymphoma 6 (BCL6) is known as a key intervention target for autoimmune diseases by inhibiting production of ROS and apoptosis (149); however, it is unclear whether this can reduce hypertension. Chen et al. recently reported that BCL6 can lower blood pressure by suppressing vascular smooth muscle cell proliferation, attenuating oxidative stress injury, and microvascular remodeling in the Ang-II induced hypertensive rats (150).

In addition, several antihypertensive drugs currently used in the clinic have a significant and specific effect on decreasing the incidence of hypertension independent of the expected mechanism. Next, we will mainly discuss the ACEI, ARB, beta-blockers, and CCBs. RAAS has a crucial part in the production of ROS during the process of hypertension. NOXs are recognized as one of most important sources of ROS in the endothelium and are mainly induced by Ang-II (149). Both ACEI and ARB can not only effectively inhibit the activity of NOXsbut improve the superoxide dismutase activity (151). In addition, they can prevent eNOS from uncoupling and enhance NO activity (152, 153). The novel beta-blockers, nebivolol and carvedilol, have been reported to have antioxidant properties. According to the results from clinical and experimental studies, these drugs have favorable protective effects on endothelial function and do not depend on the activity of beta-blockers. The antioxidant effect of carvedilol is mainly based on reducing the ROS production from inflammatory cells and the oxidation of low-density lipoprotein (LDL). Carvedilol and nebivolol could improve endothelium dependent vasodilation performance in patients with hypertension (154). Moreover, nebivolol exhibits a protective effect in the endothelial function and lowers blood pressure through suppressing the activity and expression of NADPH oxidase, thereby preventing eNOS uncoupling and promoting eNOS activity to produce more NO (155, 156). CCBs, especially dihydropyridines (like nifedipine) could directly reduce production of ROS to protect the endothelial function. CCBs have been demonstrated to prevent oxidized LDL, which can promote ROS production to trigger oxidative damage from causing endothelial dysfunction (157). Therefore, in addition to the direct effect of lowering blood pressure, dihydropyridine, CCBs play an additional antihypertensive effect by improving the function of vascular endothelial cells through antioxidation.