Classically understood to activate as the “first line” in host defense without developing memory, innate immunity is comprised of dendritic cells, natural killer cells, neutrophils, macrophages, and other granulocytes (1). Although these cells typically function in infection clearance and homeostasis, a myriad of inflammatory responses have been identified when any of these immune cells become dysregulated such as in respiratory diseases (2) and aging (3). In the context of hypertension, monocytes, neutrophils, natural killer cells, and dendritic cells have been identified as present within the kidney and contributing to blood pressure elevation through several inflammatory mechanisms (4, 5). In contrast to innate immunity, adaptive immune cells (T and B lymphocytes) are classically understood to take longer for recruitment and activation through antigen-specific interactions, resulting in formation of memory and enabling more rapid and robust response following re-challenge with the infectious agent. Further sub-categories of T cells have been identified—each fulfilling a unique and critical biological niche, including CD4⁺, CD8⁺, and CD4⁻/CD8⁻ γδ T cells, within which further sub-classes have been identified (6). T cells, in particular, have been demonstrated to play a critical role in the development of hypertension (7), but B cell involvement cannot be ruled out (8). Certain cytokines, proteins that regulate the immune cellular function, have been directly linked to pro-inflammatory immune responses; however, the specific response can vary between target cell, surrounding tissue, timing, and cytokine concentration (9). In hypertension models, many cytokines characterized classically as “pro-inflammatory” have been found to arbitrate at least some of the animal model's blood pressure elevation or organ damage, including IFNγ (10–12), TNFα (13), RANTES (14), IL-1 (15, 16), IL-6 (17), IL-17 (12), IL-18 (18), and, potentially, IL-4 (18–20). IFNγ and IL-17, especially, have been confirmed to be elevated in clinical hypertension (21). We further demonstrated that IFNγ is critical for mediating CD8⁺ T cell infiltration and interaction within the kidney, driving increased sodium retention (10). Adoptive transfer of primary CD8⁺ T cells from hypertensive mice is able to induce salt sensitivity hypertension(SSH) in WT mice, however, adoptive transfer of primary CD8⁺ T cells from IFNγ KO hypertensive mice failed to induce SSHTN in WT mice (22). Collectively these data evidence the critical role of IFNγ in mediating immune-driven hypertension. For a thorough discussion of other cytokines within the kidney contributing to hypertension, we refer the reader to this review by Drs. Wen and Crowley (23).

Cardiovascular disease is the leading global killer, and hypertension is the primary contributing cause to this premature mortality (24). Of note, untreated or unsuccessfully managed hypertension has been demonstrated to result in organ dysfunction and damage—particularly within the heart and kidney (25). Either successful reduction of blood pressure or attenuation of hypertension induced organ dysfunction are key targets to prevent this premature mortality. Reducing blood pressure globally has proven challenging: not only due to resource scarcity -be that diet or medical- in certain areas (24) but also due to the clinical findings that the origin of elevated blood pressure is unknown in 90%–95% of cases (“essential hypertension”) (26) and up to 20%–30% of patient cases are resistant to current treatments (“resistant hypertension”) (27). Although patient compliance to drug regimens complicates treatment of this disease, true diagnosis of “resistant hypertension” requires assurance of adherence to administered therapeutics; as such, other confounding factors are clearly involved (28). Furthermore, the gut microbiota may further contribute to treatment resistance through direct enhancement of drug metabolism thereby reducing therapeutic effect (29, 30).

In light of recent studies, hypertension is presently understood as an inflammatory disease, involving immune cell invasion into organ tissue resulting in a myriad of cytokine expression changes, eventually driving endothelial dysfunction and organ damage (31–34). Through a combination of depletion and adoptive transfer studies, researchers were able to identify cells from both the innate and adaptive immunity that contributed to the development of hypertension (35) and subsequent tissue inflammation, especially the contributive roles of macrophages (36) and T cells (7). Other pre-clinical studies contributed to our current understanding that dendritic cells (37–40) and neutrophils (41, 42), are also participating in the pathogenesis of hypertension. Such pre-clinical studies have been corroborated clinically through the association of pro-inflammatory biomarkers with increased risk of treatment resistant hypertension in patients with chronic kidney disease (43), an independent association between several pro-inflammatory markers and higher blood pressure in healthy patients (44), and more than 50 years of observations of a myriad of immune cells accumulating in the blood vessels and kidneys of hypertensive patients (45). The key regulatory role of the kidney in the cardiovascular system has been well established (46); as such, identifying which immune cells are infiltrating the tissue and elucidating the signaling mechanisms involved are critical in improving treatment of this non-communicable disease. Indeed, recent advances have highlighted several new molecular targets involving the immune system that may serve as new targets for the treatment of resistant hypertension (10, 28, 47), but many pathways have not yet been elucidated. Additionally, unsuccessful management of hypertension has long been associated with progression to left ventricular hypertrophy and diastolic dysfunction within the heart (48–51), and the immune system has been implicated in this progression—particularly cardiac macrophages (52). Based on the critical functions of the kidney and heart in the cardiovascular system, this review will focus on the currently understood link between specific immune cells and hypertension through their interactions with -and within- the kidneys and heart, highlighting “key players” mediating these interactions.

Kidneys and blood pressure control have been intricately linked since Guyton's studies highlighted the importance of kidneys in pressure regulation through natriuresis (53). Defects in kidney function directly correlate to blood pressure dysregulation wherein transplantation of hypertensive kidneys into normotensive animals leads to the development of hypertension within that animal (54–59). Inversely, transplantation of a normotensive kidney into a previously hypertensive animal also can attenuate previously high blood pressure (57, 58). Mechanistically, several factors within the kidneys lead to high blood pressure through inappropriate sodium handling driving greater water retention. The generation of this pathology remains incompletely understood, but several mechanisms leading to this inappropriate handling have been hypothesized ranging from microvascular modeling to the interaction of various immune cells (Figure 1) (35, 59).

During the onset of hypertension, initial high blood pressure can cause permanent damage to the nephrons through arterial injury and glomerular ischemia, which progresses to nephrosclerosis. Within spontaneously hypertensive rats (SHR), renal vascular resistance increases within the afferent renal arterioles with arterial hypertrophy resulting in glomerular ischemia and reduced glomerular filtration (60, 61). Clinical evidence correlates these findings in several patient studies linking increased arteriole pressure with elevated hyaline deposits and arteriole wall thickness, indicative of renal damage (62, 63). Lower glomerular pressure, sensed via juxtaglomerular feedback, and lower luminal chloride, sensed via macula densa (64), promote increased renin production and activation of the renin-angiotensin-aldosterone system (RAAS). Increased secretion of renin leads through a series of hormones to increased angiotensin II, which acts as a vasoconstrictor and stimulates aldosterone secretion. Aldosterone will act on the distal nephron to increase sodium and water retention thereby increasing blood pressure (65). Damage from renal ischemia due to systemic hypertension can lead to secretion of various inflammatory cytokines, which, in turn, drives infiltration of immune cells and tubular atrophy.

Concurrently, the sympathetic nervous system (SNS) also plays a role in immune cell infiltration. Sensory neurons sense changes in blood pressure leading to the activation of the SNS, and chronic activation of SNS may lead to the development of hypertension as described in these reviews referenced here (65–67). One such experiment by Xiao et al., found that renal denervation blunted immune activation and blood pressure elevation in mice receiving angiotensin II (68), indicating some neural regulation of inflammation in hypertension. SNS activation also leads to increased release of renin, which elevates the blood pressure sensed by the kidney and is hypothesized to stimulate prostaglandin production (69). Catecholamines signal through the β2-adrenergic receptors on innate and adaptive immune cells which are involved in the development of cancer and autoimmune disorder. However, the clear pathway of how Catecholamines regulates immune cells is still unknown (65). Overall, overactivation of the SNS is often seen with hypertension, and its activity can lead to cytokine production and release (e.g., IFNγ and/or TNFα), which is associated with various tissue and organ damage in hypertensive patients resulting in subsequent damage as both the innate and adaptive immune systems accumulate and are key players in kidney damage (7, 35, 68, 70–75). An inverse relationship wherein inflammation influences nervous system function and signaling has been observed in viral infection (76), endometriosis (77), and arthritis (78). Considering the interplay between SNS activity and hypertension, it is possible that renal inflammation may, in turn, dysregulate SNS function in a feedback loop; however, further research is necessary to confirm if this relationship exists in hypertension.

Prostaglandins(PGs), which increase in production with salt loading, indirectly reduce sodium reabsorption and contribute to vasodilation beneficial for hypertensive individuals (65). In addition to their beneficial effects, PGs also increase vascular permeability and their chemotactic activity may attract leukocytes to the locally inflamed zone (79). Moreover, PGE2 has been found to stimulate IFNγ receptor expression on human lymphocytes (80), further implicating IFNγ signaling mechanisms in inflammation and hypertension. PGE2 has been shown to increase blood pressure and disrupt endothelial signaling in EP2/4 (E-prostanoid receptor) deficient mouse models (81–83) or in the presence of enhanced EP3 expression (84, 85), complicating the role of prostaglandins in hypertension.

Depletion of mononuclear phagocytes (MPs, includes macrophages and dendritic cells)) with liposome-encapsulated clodronate reduces fibrosis and glomerular sclerosis typical of salt-sensitive hypertension models (86). Activation of these cells can stem from a variety of effectors from the high salt environment to the activity of the SNS (68, 75, 87). High salt, specifically high sodium rather than high chloride or high osmolarity, triggers a pro-inflammatory state similar to the macrophage M1 state through p38 and ERK (87). Interestingly, this specific activation does not completely match the pro-inflammatory macrophage response seen with LPS stimulation. Macrophages activated by LPS eventually resolve towards an anti-inflammatory state whereas high salt-activated macrophages experienced suppression of this resolution (87). Activated MPS within hypertension leads to ROS production and generation of the cytokines IL-1β and TNFα (88), which is covered in greater detail in this review referenced here (89). Tubular IL-1β, in particular, has been demonstrated to recruit macrophages to the kidney leading to upregulation of ENaC and salt-sensitive hypertension in diabetic mice which are characterized by renal inflammation (16). By knocking out the IL-1R receptor in immune cells or knocking down IL-1β, the authors were able to prevent the switch to pro-inflammatory macrophages thereby preventing macrophage induced salt-sensitivity (16). Additionally, mineralocorticoid receptor may also participate in activated MPs-induced fibrosis during acute kidney injury (AKI), because mineralocorticoid receptor antagonist Finerenone providing protection against this development of renal fibrosis (90); SGK1, a commonly known downstream signaling molecule of ROS and mineralocorticoids, has also been linked to antigen presentation as a salt sensor in CD11c⁺ cells (expressed on dendritic cells or macrophages) (91) which leads to an increase in Epithelial sodium channel (ENaC) in these cells (92). Upregulation of ENaC in CD11c⁺ cells, in turn, correlated with increased activation, NADPH oxidase expression, and isolevuglandin-protein adducts (92).

Bridging the gap between innate and adaptive immunity, high salt not only promotes activation of MPs but also leads to the formation of isolevuglandins, also referred to as isoketals (37, 92). Isolevuglandins are a product of arachidonic acid generated as the result of oxidative stress, which is both a product of -and contributor to- hypertension and renal dysfunction (93). Harrison and colleagues identified the accumulation of isolevuglandins during hypertension and the development of these into neoantigens by dendritic cells. Hence, these dendritic cells have the capability of presenting isolevuglandins to T cells leading to their activation, which plays an important role in the changes within the kidney during hypertension (37).

In his landmark study, Guzik et al., demonstrated adoptive transfer of T cells restored the hypertensive response to angiotensin II in RAG1^−/– (immunodeficient) mice (7). Many other studies confirmed the critical role of the T cell in the development of hypertension, including alternative animal models (94). De Miguel et al., for example, found that T cells invaded into the kidney of Dahl salt-sensitive rats on high salt diet, and administration of the immunosuppressant tacrolimus blunted T cell invasion within the kidney, reduced renal damage, and lowered blood pressure (95). Subsequent studies were conducted to identify the specific subtypes of contributing T cells, resulting in the identification of a variety of T cells that become active within hypertension including γδ, CD4⁺, and CD8⁺ T cells (5). γδ T cells hold the most similarities with the innate immune system and are capable of antigen presentation. Within hypertension, these γδ T cells as well as CD4⁺ T cells function by aiding in the activation of CD8⁺ T cells or through cytokine production, including IFNγ and IL-17A (5). In particular, γδ T cell deficient mice showed blunted hypertensive response and endothelial dysfunction to angiotensin II, and increased numbers of these T cells have been found in the spleens of hypertensive mice (96).

CD8⁺ T cells not only contribute to cytokine production in general inflammatory responses but we also found they interact directly with the nephron to increase sodium retention by stimulating an increase in the sodium chloride cotransporter (NCC) in the DOCA + salt model of hypertension (97). Additionally, splenic CD8Ts from hypertensive mice can generate salt sensitive hypertension in recipients (97). We further found the cytokine IFNγ was critical for this infiltration to take place in the DOCA + Salt model (10) and adoptive transfer models of hypertension (22). Of note, IFNγ from CD8⁺Ts stimulates the IFNγ receptor expressed within the distal convoluted tubule to promote interaction between the CD8⁺T and tubule (10). Additionally, Carnevale et al., found CD8Ts not only increased resistance in arteries in a three-dimensional culture model of hypertension but also exhibit enhanced gene pathway upregulation to chemotaxis and response to IFNγ in pre-hypertensive mice (98). The crucial role of IFNγ—along with IL-17—in immune-cell mediated hypertension was previously characterized by Kamat et al., in the angiotensin II model of hypertension (12). Clinically, hypertensive human CD8⁺T IFNγ production and CD4⁺T IL-17 has been found to be significantly elevated (21). Youn et al., also found pro-inflammatory immunosenescent CD8⁺Ts (expressing higher perforin, granzyme B, IFNγ, and TNFα) are increased in peripheral blood of hypertensive patients (99).

Within CD8⁺ T cells a variety of memory populations are generated upon activation including an effector memory T cell population that can enter and exit from lymphoid tissue to non-lymphoid tissue. Once activated, these T cells remain primed to the stimulus and become easier to activate. In a variety of models, several studies have found a dendritic cell-mediated increase in this effector memory population during hypertension (100–102). Trott et al., confirmed that an oligoclonal population of CD8⁺Ts can be found in the kidney of angiotensin II-induced hypertensive mice (103); however, the subtypes of CD8⁺Ts present have not yet been characterized. The development of these populations lead to the potential for continual T cell activation and the exertion of their effects on the kidney. Accordingly, outside of the physical damage due to the high pressure within the kidney, CD8⁺ T cells may have a long-lasting ability to become activated and lead directly to the inappropriate sodium handling within the nephron that drives water retention.

Regulatory T cells (T_regs)—CD4+ T cells that express CD4, CD25, and FOXP3—are classically understood to reduce inflammation and play an anti-proliferative role in immune responses (104); as such, these cells may play a protective role in the kidney during the development of hypertension. Expansion of T regulatory cells through low-dose IL-2 administration has been shown to lower blood pressure induced via systemic lupus erythematosus in mice; as such, these cells may play a protective role in hypertension (105). Indeed, increased numbers of T_regs in female rats may explain the reduced DOCA + Salt induced hypertension in female rats compared to males, and depletion of T_regs increased female but not male rat blood pressure elevation and renal fibrosis to DOCA (106). Such a protective role may involve an immunosuppression independent mechanism; as such, further research is needed to clarify the protective, antihypertensive role of regulatory T cells in the kidney (107).

In addition to T cells, B cells have been observed to increase within- and invade- the hypertensive kidneys. B cells alone may not lead to the development of hypertension, as adoptive transfer of T cells and not B cells from hypertensive mice into normotensive Rag1^−/– mice (which lack B and T cells) resulted in hypertension (7). However, in mice that lack mature B cells through B-cell activating factor receptor deficiency, hypertension was attenuated in the Ang II model (8). B cells play a role in the accumulation of MPS and T cells, which may lead to the kidney pathologies observed during hypertension.

Chronic hypertension has been identified as the leading cause of congestive heart failure (108). The progression of hypertension into cardiac dysfunction, and that of cardiac dysfunction into heart failure, is a multi-faceted progression which often involves morphological and molecular biological changes in the cardiomyocytes, alterations within the surrounding microenvironment, and physical changes to the heart. In addition to playing a role in the perturbation of blood pressure, often through salt-sensitive inappropriate sodium handling (109), decades of research have shown that immune cells are partially culprit in the onset of hypertension, the progression of cardiac dysfunction to heart failure and, possibly, even the progression of hypertension to cardiac dysfunction (41).

Either hypervolemia or increased peripheral resistance increase the pumping force requirements of the heart, especially within the left ventricle (110), to overcome the pressure in the aorta to successfully deliver blood to the rest of the body. This increase in pressure within the ventricle causes excessive stretching, resulting in cardiomyocyte injury and subsequent cardiac hypertrophy—a process mediated by the immune system (111). Furthermore, immune regulation of T cells, macrophages, fibroblasts, and dendritic cells all play a role in the worsening of cardiac function in hypertension and heart failure; as such, immunological targets appear to be promising targets to increase heart health and function in treatment of heart disease (112).

Collagen deposition in cardiac fibrosis plays an important role in the maintenance of the heart. Fibrosis functions in both maintaining homeostasis—especially within the interstitium—and in repairing physical injury that occurs. Fibrotic remodeling is a complex function that involves the secretion and deposition of connective molecules, most importantly Collagens I and III, into the interstitial and perivascular spaces. However, excessive deposition of these connective molecules can impair cardiac function. The increased deposition of molecules within the extracellular matrix (ECM) stiffens the heart chambers, thereby inhibiting the heart from expanding and contracting efficiently, and, ultimately, resulting in increased cardiac stress to maintain homeostatic output. As this fibrotic deposition progresses, cardiac output becomes sufficiently reduced to cause damage to other organs and damage to cardiac cells due to impaired circulation and increased pressure, a pathology so common that 50% of heart failure patients present with this increased cardiac load due to fibrosis (52, 113). Therefore, preventing fibrosis in heart failure remains an attractive target to help preserve cardiac function.

Matrix Metalloproteinases (MMPs) are a family of proteins that help regulate ECM deposition and degradation, many of which are produced by macrophages and other immune cells (114). In particular, MMP-9 has been implicated in a wide range of functions, including the degradation of ECM (115). During cardiac dysfunction, when the fibrotic response is excessive, MMP9 is produced to chaperone the correct degradation and disposition of molecules for proper ECM development and scar formation. However, it has been noted that the expression of MMP9 is reduced in patients with congestive heart failure (116), potentially indicating an impaired ability to degrade excess collagen and further highlighting the importance of extracellular matrix homeostasis.

Macrophages, originating from monocytes found in the circulation, express a variety of markers and serve a great deal of roles in innate immunity as well as mediate adaptive immune response by cross-talking with B and T cells (117). These cells are recruited to injured or infected cells via chemokine signaling (e.g., CCL2,CXCL1, CX3CL1) from a number of other cells including fibroblasts, endothelial cells, and epithelial cells (118). Of note, cardiac-resident macrophages appear to play a more protective role against fibrosis than monocyte-derived macrophages that infiltrate the heart and promote hypertrophy, but further research is needed to clarify the distinction in responses between monocyte derived macrophages and cardiac resident (119). There are traditionally understood to be two main macrophage phenotypes: M1 and M2 (120).

M1 macrophages are considered “traditionally activated” and become active upon exposure to IFN-γ and TLR stimulation (120). These macrophages are considered pro-inflammatory and secrete inflammatory cytokines such as IL-1β, TNF, and IL-12 (121). In a neonatal injured heart model, inhibition of cyclooxygenase-2 resulted in increased M1 macrophage recruitment at the wound site which may contribute to the treatment induced suppressed cardiac hypertrophy and fibrosis (122); however, resolution-phase macrophages can exhibit M1 markers yet express a unique inflammatory phenotype (123), making the role of M1 macrophages in cardiac fibrosis unclear. Depletion of macrophages (both phenotypes) has been shown to reduce cardiac remodeling in the Dahl salt-sensitive rat (124), but did not identify the key contributing phenotype.

In contrast to M1 macrophages, M2 macrophages are anti-inflammatory and pro-fibrotic in function; as such, the M2 phenotype may especially contribute to the fibrogenesis in hypertensive hearts.

M2 macrophages are “alternatively activated”(activated by IL-13, CSF-1, IL-4, IL-10, and TGF-β) (121, 125, 126). These cytokines, commonly produced by Th2 T cells, have been shown to be directly linked to the production of collagens and the onset of fibrosis (126), potentially through their stimulation of M2 macrophages. Furthermore Angiotensin II and cations have been implicated in the transition of fibroblasts to myofibroblasts capable of collagen production and deposition (127). The M2 macrophage, alone, is not capable of depositing the collagen seen in fibrosis; rather, these cells are able to promote the transition of the homeostatic fibroblasts into fibrosis-inducing myofibroblasts (128). Macrophages, once activated at the site of injury, can recruit more macrophages and circulating fibroblasts, leading to increased inflammation and fibrosis (127).

M2 macrophages induce myofibroblast differentiation through a number of mechanisms such as the production of TGF-1β. A recent study by Murray et al., implicated IL-13, TGF-β1, and CCL2 axis in the hyper-stimulation of myofibroblasts in a model of idiopathic pulmonary fibrosis with a usual interstitial pneumonia pathology (IPF/UIP) (129). IL-13, TGF-β1, and CCl2 together appeared to result in a synergistic effect in the activation of myofibroblasts. Though these results have not been explored in the heart specifically, they indicate the M2 macrophage can exacerbate organ fibrosis, which may be relevant in hypertension and heart failure through the same myofibroblastic axis.

Systemic administration of any drug will be expected to result in eventual off-target effects (155); as such, it should be unsurprising to consider that systemic administration of antihypertensives may result in alterations of off-target organ -or cellular- functions. Although such unintended molecule-receptor interactions are typically referred to as toxicities, it is also possible that the desired phenotype (i.e., lowering blood pressure) may be achieved through some of these very same “unintended” effects. To this end, it can become relevant to consider if receptors targeted by antihypertensives are also expressed and functional on other cells—such as immune cells that play a critical role in the development of hypertension (31, 35, 156). An excellent discussion by Felkle et al., regarding the role of ACEi, ARBs, CCBs, β-blockers, and thiazides in immune function modulation can be found referenced here (157). For the purpose of this review, we will provide a brief outline of several receptors and current understanding of expressing immune cell types and potential contributing mechanisms (Figure 4).

Clinically, elevated immune cell activation/function of CD3⁺/CD4⁺ (191), CD3⁺,CD8⁺ (99), and monocytes (192) have been described in hypertension. Upregulation of the cytokines IL-17 and IFNγ (21), IL-6 and TNFα (44), and IL-18 (18), has been correlated with clinical manifestation of essential hypertension, among other cytokines (193). To this end, targeting the immune system to reduce cytokine production and immune cell activation and infiltration may reduce blood pressure and subsequent tissue damage. This excellent review by Murray et al., describes the effects of immunosuppressants on blood pressure in animal models (193); however, clinical trials have been complicated through the nephrotoxic (and other tissue) effects of several immunosuppressants -such as calcineurin inhibitors- resulting in blood pressure elevation driven by tissue damage and sodium transporter upregulation (194–196). Our lab has recently identified the critical role tubular PD-L1 plays in mediating CD8⁺T-distal convoluted tubular interaction and hypertension; by knocking down PD-L1 in mice using renal tubule specific nanoparticles (197, 198) we were able to blunt blood pressure elevation in the DOCA + salt or adoptive transfer models of hypertension, identifying another potential therapeutic target (10). Further studies are needed to address the potential effectiveness of alternative immunosuppressant therapies in reducing blood pressure. Several promising pre-clinical studies have been conducted indicating the feasibility of using FDA-approved nanodrug platforms to deliver tissue specific immunosuppressant therapy (minimizing off-target toxicities), but further validation and studies are required before use in a clinical setting (199). Regardless of current difficulties, targeted immunosuppression to reduce inflammation and immune-mediated organ dysfunction in hypertension continues to be of scientific interest.

The immune system plays a role in the pathogenesis of hypertension through several inflammatory signaling mechanisms involving cells from both the innate and adaptive immune system; however, the signaling molecules and pathways governing these interactions have proven to be complex and not yet fully understood. Within both the heart (109) and kidney (200), current data suggests higher pressure can, alone, drive immune infiltration and subsequent inflammation within the invaded organ leading to dysfunction. Immunodeficient mice (Rag2^−/−) exhibited reduced pressure-driven cardiac remodeling (109), and the immunosuppressant tacrolimus reduced T cell infiltration, renal damage, and blood pressure elevation in the Dahl salt-sensitive rat on high salt diet (95). The immune system not only contributes to blood pressure elevation (35) but also mediates organ dysfunction and dysregulation initiated by elevated blood pressure (94). This inextricable connection between immunity, hypertension, inflammation, and organ dysfunction lends high priority to targeting the immune system to lower blood pressure or, at least, reduce inflammation due to hypertension (47). Even current FDA approved anti-hypertensives may mediate some of their beneficial effects through immune modulation, but further studies are needed for confirmation (157). Targeting the immune system to lower blood pressure and reduce organ damage has proven complicated (201, 202), but organ specific immune targeting using nanotechnology appears to be a promising solution to reduce toxicities (155, 199). Recent identification of single nucleotide polymorphisms in SH2B adaptor protein 3 contributing to T cell involvement in hypertension and renal damage (203) further complicates therapeutic targeting as genetic mutations may predispose certain immune cells to promote inflammation, supporting consideration of individual patient genetic predispositions when identifying driving factors of hypertension to design future treatment plans, as is becoming increasingly debated (204). As contributing immune players and inflammation-mediating molecules are characterized, novel pathways can be identified and targeted therapeutically to lower blood pressure and attenuate hypertension-mediated organ dysfunction. Recent studies have highlighted several such immunity-associated relevant receptors or cytokines and confirmed their relevance in several animal models of hypertension.