**2. Immune system and inflammation in hypertension**

#### **2.1 Inflammation and immunity basics**

Inflammation is an immune system response to noxious stimuli entered or occurred in a tissue that includes pathogens, damaged cells, toxic compounds, or irradiation; and inflammation acts to remove the noxious agent and to initiate healing process. At tissue level, inflammation is characterized by swelling, redness, heat, pain, and loss of tissue function, which are considered five cardinal signs of inflammation, and these signs result due to local immune, vascular, and inflammatory cells response to infection or injury [12]. In addition to infection and tissue injury, inflammation can be initiated due to disruption of cellular and tissue homeostasis. It has been shown that cells with disrupted homeostasis that undergoes senescence release inflammatory mediators known as the senescence associated secretory phenotypes (SASP). While excessive cell stress such as ER, mitochondrial or osmotic stress that cannot be handled by effector mechanisms within homeostatic regime activates NLRP3 inflammasome [13]. Recently, researchers are mentioning inflammation as a spectrum of a system (organism, tissues, cells) state; homeostatic state, stress response state, and inflammatory state. Indeed, both stress response and inflammation are engaged to eliminate the stressor (i.e., the source of perturbation), to promote adaptations to the stressor, and ultimately to return the system to the homeostatic state [14]. Deviations of regulated variables within a normal range are corrected by the homeostatic circuit (including stress responses) while extreme deviations of regulated variables beyond the homeostatic range trigger the inflammatory response [13]. At the same time,

it is important to notice that even though inflammation brings homeostatic state at the end, inflammation and inflammatory mediators are both antagonistic to and dominant over homeostatic signals [14].

Thus, inflammation can be induced by extreme deviations in regulated variables of cellular and tissue homeostasis or by agents that cause disruption of tissue homeostasis, including pathogens, toxins, and xenobiotics [14]. The inflammation process is coordinated by a large range of mediators that form complex regulatory networks. Inflammatory pathway is composed of inflammation inducers, inflammation sensors, inflammation mediators, and inflammatory effectors [15].

Inflammation is a component of the broader and wider immune system. The immune system is composed of a complex network of specialized cells where each type has precise roles. The immune system is an interactive network of lymphoid organs, cells, humoral factors, and cytokines [16]. The immune system has two lines of defense, innate immunity, and adaptive immunity. Innate immunity is nonspecific defense mechanism which is used by the host immediately or within hours of encountering an antigen. It comprises four types of defensive barriers: anatomic (skin and mucous membrane), physiologic (temperature, low pH, and chemical mediators), endocytic and phagocytic, and inflammatory [17]. Innate immunity relies upon a repertoire of germline-encoded receptors, the pattern recognition receptors (PRRs) that recognize the pathogen-associated molecular patterns (PAMPs) to detect microbial structures and the damage-associated molecular patterns (DAMPs) to detect immunological danger (molecules released during the cell lysis and tissue damage) [18]. Innate immunity rapidly recruits immune cells to sites of infection and induces inflammation through the production of cytokines (tumor necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6)) and chemokines [17]. Moreover, innate immunity is considered as an ingenious doorbell that awakens the adaptive immune response through antigen-presenting cells (APCs) such as dendritic cells (DCs) that present antigens to the lymphocytes (with the optimal T cell receptor (TCR) specificity and affinity) and also costimulatory signals, which guarantee full proliferation and differentiation of the lymphocytes [19]. Adaptive immunity consists of two broad sets of antigen-responsive cells, the B and T lymphocytes. B lymphocytes are the precursors of antibody-producing cells, plasma cells. Antibodies are capable of recognizing three-dimensional structures and thus can interact with and lead to the neutralization of pathogens in extracellular fluid. By contrast, the T cell antigen recognition system recognizes a complex consisting of an antigenderived peptide bound into a specialized groove in class I and class II major histocompatibility complex (MHC) molecules of APCs [20]. CD8+ T cells can interact with peptides (9–11 amino acids in length) on almost any cell expressing MHC class I while the TCRs of CD4+ T cells engage peptides bearing MHC class II. The activated T cells can play direct roles in elimination of pathogens by killing infected target cells, they can function by providing cognate (involving direct cellular contact) or cytokine signals to enhance both B- and T-cell responses, as well as causing activation of mononuclear phagocytes, and also T cells regulate immune responses, limiting tissue damage incurred by means of autoreactive or overly inflammatory immune responses [21]. In adaptive immunity, long-lived memory cells (memory lymphocytes) ensure that a second encounter with the same invader is dealt with swiftly and effectively because of the greater number (for the given antigen), extended lifespan, more rapid response rate, superior proliferation capacity, and wider access to tissues of the memory lymphocytes [19].

#### **2.2 Inflammatory cytokines in hypertension**

Inflammation plays a vital role in preserving physiological homeostasis of an organism, in protection against invading agents such as bacteria and virus, and in healing processes of damaged tissue. On the other hand exaggerated inflammation or chronic inflammation can cause tissue damage, and contributes for the development and/or persistence of many diseases [22]. Acute inflammatory response can be initiated during times of infection or in response to physical, chemical, or metabolic noxious stimuli through interaction between pattern recognition receptors expressed on innate immune cells and PAMPs or DAMPs. On the other hand, chronic low-grade systemic inflammation is typically triggered in the absence of an acute infectious insult [23].

Chronic low grade systemic inflammation is a low-grade, systemic, unresolved, and smoldering chronic inflammation clearly indicated by a 2- to 4-fold increase in serum levels of inflammatory mediators, including interleukin-6 (IL-6) and acute phase proteins, for example, C-reactive protein (CRP); even though there is no numerical cut off values for elevated inflammatory mediators to define chronic low grade systemic inflammation at the present time [24]. In chronic low grade systemic inflammation, besides CRP and IL-6, a large number of cellular (total leukocytes, granulocytes, and activated monocytes) and pro- and anti-inflammatory mediators including IL-1, IL-8, IL-13, IL-18, interferon-α and interferon-β, tumor necrosis factor, CC chemokine ligands, adhesion molecules, and acute-phase reactants (serum amyloid A, and fibrinogen) are involved or are produced as a result of the inflammatory processes. Chronic low grade systemic inflammation is associated with many chronic disease conditions including CVDs, neurodegenertion and Alzheimer's disease, insulin resistance and type 2 diabetes mellitus, tumorigenesis and cancer, osteoporosis, anemia, chronic kidney disease, depression, sarcopenia, and disability [25].

Whereas hypertension has predominantly been ascribed to perturbations of the vasculature, kidney, and central nervous system, researches have shown that the immune system also contributes to this disease. Inflammatory cells that accumulate in the kidneys and vasculature of humans and experimental animal models with hypertension likely contribute not only for pathogenesis of hypertension but also contribute to end-organ damage [26].

An association between hypertension and inflammation has been clearly demonstrated while it is not clear whether inflammation is predominantly a cause or an effect of hypertension [11]. Many studies indicated that an inflammatory marker CRP level increases as blood pressure level increases. A prospective follow up study done on 15, 215 women found that, in cross-sectional analyses of baseline data of the study, increasing categories of blood pressure were significant predictors of CRP levels; meaning linear increase in levels of CRP was seen as levels of systolic blood pressure or diastolic blood pressure increases [27]. Another case-control study done among 904 participants, 39–50 years old, found a continuous, independent association between serum CRP and elevated blood pressure. The study also reported that, after adjustment for sex, obesity, race, serum insulin level and family history of coronary heart disease, odds ratios for hypertension increased progressively across CRP quintiles; participants in the highest CRP quintile were 2.35 times more likely to have hypertension than those in the lowest quintile [28]. Similarly, a case-control study done on 1529 subjects (767 hypertensive and 762 non-hypertensive) aged from 30 to 84 years, reported that the means for BP and CRP in cases (hypertensive subjects)

were significantly higher than that in controls (non-hypertensive subjects) [29]. A study carried out on 335 non-hypertensive study participants, with mean arterial blood pressure of 135/85 mmHg and age of 65 years at base line, indicated that the 2-year risk for new-onset hypertension was 18% greater for 1 mg/l increment of CRP after adjustment for low-density lipoprotein cholesterol and BMI [30]. A prospective cohort study done on 20,525 female USA health professionals aged 45 years or above found that the adjusted relative risk (RR) of developing hypertension is 1.5 for the group with the highest level of CRP at base line compared with the group of the lowest CRP at the base line. From their cohort study, the study group concluded that CRP levels are associated with future development of hypertension [31].

Similar to association trend observed between CRP and blood pressure, higher level of other pro-inflammatory cytokines were reported among hypertensive population or individuals with higher blood pressure (BP) levels compared with non-hypertensive population or individuals with lower BP levels. A study done on 79 hypertensive and 117 non-hypertensive study subjects showed that plasma Il-6 and TNF-α were significantly higher (two to four times higher) in hypertensive subjects compared to non-hypertensive subjects [32]. Similarly, another study that assessed association of blood pressure level with plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and interleukin-6 (IL-6) among 508 apparently healthy men, found increasing levels of SBP, pulse pressure (PP), and mean arterial pressure (MAP) were significantly associated with increased levels of sICAM-1 while all blood pressure parameters (SBP, DBP, PP, MAP) were significantly associated with increasing levels of IL-6 [33]. Two independent studies that compared the serum and the peripheral blood mononuclear cells (PBMCs) IL-1β levels among hypertensive and non-hypertensive groups found significantly higher level of IL-1β among hypertensive groups [34, 35].

Experimental studies on animals also confirmed association between hypertension and inflammation. An experimental study that compared blood pressure levels among angiotensin II (Ang II) infused mice (wild type mice versus IL-6 deficient mice (IL6−/−) found that in wild-type mice systolic blood pressure began to increase by day 3, increased significantly by day 7, reached a peak by day 10, and continuously maintained high blood pressure through the end of 2-week Ang II infusion while genetic deletion of IL-6 in mice led to a significant reduction of Ang II-induced hypertension [36]. Another experimental study showed that RNA interference knockdown of IL-6 in Sprague-Dawley rats abolished the cold-induced upregulation of IL-6 in kidney and aorta, and also significantly attenuated cold-induced elevation of systolic blood pressure [37].

An experimental study that compared effect of Ang II to infusion into wild types (WT) mice and TNF-α knockout (KO) (TNF-α−/−) mice found that Ang II infusion for 14 days significantly increased mean arterial pressure in WT mice from (115 ± 1 to 151 ± 3 mmHg) but not in TNF-α−/− mice (113±2 to 123±3 mm Hg). The study also showed that, when TNF-α−/− mice are given replacement therapy with human recombinant TNF-α, Ang II administration caused an increase in mean arterial pressure (109 ± 1 to 153 ± 3 mm Hg) [38]. Another experimental study done on mice, which compared blood pressure level among angiotensin II infused WT mice and type 1 interleukin-1 receptor (IL-1R1)-deficient (KO) mice showed that during chronic Ang II infusion, the IL-1R1 KO animals were partially protected from hypertension compared to the WT controls (165±6 versus 180±3 mmHg). The study also reported administering an IL-1R1 antagonist (anakinra) or vehicle to WT mice for 3 days prior to and during chronic Ang II infusion resulted in IL-1R1 blockade with anakinra

significantly attenuated the level of blood pressure elevation during chronic Ang II infusion (154 ± 4 versus 167 ± 3 mmHg). Both isoforms of IL-1 (IL-1α and IL-1β) bind and signal via the IL-1R1 [39].

An experimental study that investigated effect of a proinflammatory cytokine interleukin 17 (IL17) reported that initial hypertensive response was similar for wild type mice (C57BL/6J mice) and interleukin 17 deficient mice (IL17−/− mice) however hypertension was not sustained in IL17−/− mice, reaching levels 30 mmHg lower than in wild type mice by 4 weeks of angiotensin II infusion. Moreover, blood vessels from IL17−/− mice displayed preserved vascular function, decreased superoxide production, and reduced aortic T cell infiltration in response to angiotensin II infusion which is indicative for importance of IL17 for the maintenance of angiotensin II-induced hypertension and vascular dysfunction [40].

#### **2.3 Innate and adaptive immunity cells in hypertension**

In addition to above mentioned human and animal studies that showed association between inflammatory cytokines and hypertension, many studies implicated that both innate and adaptive immunity cells play roles in hypertension pathophysiology.

Variability, diversity, and joining (V(D)J) recombination is the specialized DNA rearrangement used by cells of the immune system to assemble immunoglobulin and T-cell receptor genes from the preexisting gene segments. The RAG1 and RAG2 proteins are the only lymphoid-specific factors needed for V(D)J recombination that generate diverse B-lymphocytes antibodies and T-cell receptors [41]. An experimental study on mice showed that in mice with genetic deletion of the recombinase-activating gene (RAG-1−/−) mice, mice that lack both T and B lymphocytes, hypertension caused by chronic low-dose angiotensin II infusion was markedly blunted. Similar to response for angiotensin II infusion, in the experimental study, the increase in blood pressure was also blunted in RAG-1−/− mice in desoxycorticosterone acetate (DOCA) – salt hypertension model, indicating that lymphocytes likely play a role in different types of hypertension. Besides, in the RAG-1−/− mice study, adoptive transfer of B cells into RAG-1−/− mice had little effect on the increase in blood pressure while adoptive transfer of T cells restored the hypertension response to angiotensin II infusion. This study indicated that the T lymphocyte plays a critical role in the development of hypertension [42].

A study done on mice showed that infusion of angiotensin II for 14 days into wild type (WT), CD4−/−, and CD8−/− mice resulted in blunted blood pressure increase in CD8−/− mice while WT and CD4−/− mice exhibited increased blood pressure in response to angiotensin II. The study also reported that an increase in blood pressure in response to deoxycorticosterone acetate (DOCA)-salt challenge was significantly reduced in CD8−/− mice compared to either CD4−/− or WT mice, similar to angiotensin II-induced hypertension response [43]. It is known that mice lacking CD4 (CD4−/− mice) also lack regulatory T cells (Tregs) which may predispose to aggravated hypertension in CD4−/− mice in the above mentioned experimental study [43].

Osteopetrotic (Op/Op) mice have no colony-stimulating factor 1 gene and thus they lack colony-stimulating factor l (CSF-1), and are functionally deficient in macrophages [44]. In an experimental study done on adult Op/Op, heterozygous (Op/+), and wild type (+/+) mice, infusion of Ang II for 14-days resulted in significantly increased blood pressure in wild type (+/+) and heterozygous (Op/+) mice while blood pressure in Op/Op remained unaffected from base line level [45]. Similarly, in a study where Op/Op, heterozygous (Op/+), and wild type (+/+) mice given deoxycorticosterone acetate (DOCA)-salt for 14 days, systolic blood pressure (mmHg) was significantly increased (146 +/− 2 and 138 +/− 1; P < 0.001 vs. basal 115 +/− 3 and 115 +/− 3) in wild-type (+/+) and heterozygous (Op/+) mice respectively, but not in Op/ Op mice (130 +/− 1 vs. basal 125 +/− 3) [46].

In an experimental study which selectively ablated lysozyme M-positive (LysM+) myelomonocytic cells by low-dose diphtheria toxin in mice with inducible expression of the diphtheria toxin receptor (LysM iDTR), thus the experimental group of mice have reduced number of monocytes in the circulation of the mice without affecting number neutrophils, showed that attenuated Ang II-induced blood pressure increase among experimental group compared to control group [47].

Activation of T cells requires two signals; the first involves interaction of the T cell receptor with an antigenic peptide presented in the context of major histocompatibility complex on antigen-presenting cells (APCs) while the second, referred to as costimulation, involves the simultaneous interaction of receptors in proximity to the TCR with ligands on the APC. Among several potential costimulatory interactions, the binding of T cell CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (CD152) with B7 ligands CD80 and CD86 on APCs is important, particularly for activation of naïve T cells [48]. A study done on mice showed that blockade of B7-dependent costimulation of T-cells with CTLA4-Igl reduced both angiotensin II- and DOCA-salt induced hypertension. Moreover, in mice lacking B7 ligands (B7−/− mice), due to genetic deletion of both CD80 and CD86, angiotensin II caused minimal blood pressure elevation and vascular inflammation, and these effects were restored by transplant with wild-type bone marrow. This study indicated that stimulation of T-cells by dendritic cells is important in both angiotensin II- and DOCA-salt induced hypertension [49].

A study was done on mice that are genetically deficient of B cells, B-cell–activating factor receptor-deficient (BAFF-R−/−) mice, showed that while Ang II infusion caused a rapid rise in SBP from 117 ± 3 mmHg at baseline to a maximum level of 165 ± 5 mmHg by day 21 in wild type mice, the pressor response to Ang II was attenuated in BAFF-R−/− mice with SBP reaching a maximum of only 149 ± 4 mm Hg at day 21 and remaining at this level until day 28 from the base BP level 112 ± 3 mm Hg. Moreover, the study showed that the introduction of B cells into BAFF-R−/− mice were sufficient to fully recapitulate the pressor response to Ang II to levels observed in wildtype mice. This study demonstrated that B cells are crucial for the development of Ang II-induced hypertension [50]. Mutations in the BAFF-R are associated with B-cell lymphopenia and antibody deficiency.

In an experimental study done on Ang II-induced hypertension mice model, mice injected with CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) and infused with hypertension doses of Ang II (400 ng/kg/min) for 2 weeks showed significantly lower increment in blood pressure compared with mice that infused only hypertension doses of Ang II [51]. Similarly, another study on mice reported that mice injected CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) three times, at two-week intervals and then infused with Ang II for 14 days showed blunted increase of SBP compared with control group (group that did not receive regulatory T cells) [52]. In another experimental study that compared blood pressure change among mice received aldosterone infusion and 1% saline in drinking water, mice that infused with aldosterone and received Treg cells adoptive transfer did not show significant increase in both systolic and diastolic blood pressure when compared with control group mice (control mice were similarly injected intravenously with vehicle and received tap drinking water); while mice group that was infused with aldosterone and given 1% saline in drinking water without receiving Treg cells showed significant increase in

both systolic and diastolic blood pressure compared to control group [53]. On contrary to the above mentioned study results one experimental study on mice reported that mice that received Treg cells and infused with Ang II showed similar incitement in blood pressure with group of mice that infused Ang II without receiving transfer of Treg cells [54]. The different results of the latter study may be due to differences in experiment procedures as all former studies performed Treg cells transfer few weeks before infusion of Ang II or aldosterone while the latter study performed Treg cells transfer and Ang II infusion simultaneously.

Thus, the existing body of knowledge clearly confirmed existence of association between immune system activation and hypertension while ascertaining the cause effect relationship between inflammation and hypertension needs further study.

#### **2.4 Mechanisms that underlie association between immune system perturbation and chronic inflammation, and hypertension**

An individual's blood pressure is largely determined by the functions of three key organs, namely the heart which pumps blood through the circulatory system, the blood vessels which regulate blood flow through the organs and the whole body, and the kidneys which regulate sodium and water excretion and hence blood volume. The maintenance of physiological blood pressure levels involves coordinated control and regulation from neurohormonal system which includes the renin-angiotensinaldosterone system (RAAS), the natriuretic peptides and the endothelium, the sympathetic nervous system (SNS) and the immune system on functions of the heart, blood vessels and the kidneys. Perturbation in function of organs or systems that are involved in BP control can directly or indirectly lead to increase in blood pressure that ultimately ends up in the development of hypertension, and over time results in target organ damage such as, left ventricular hypertrophy and chronic kidney disease (CKD) and CVD outcomes [55].

Existing observational and experimental studies highlight that in some hypertensive patients at least, additional drivers of hypertension must exist than the already known mechanisms involved in pathophysiology of hypertension, and new targets must be defined [10]. Inflammation and immune system perturbation are likely contributors in the development and sustaining of hypertension. The current overarching hypothesis about inflammation and immune system involvement in pathophysiology of hypertension is that immune cells accumulation in blood vessels (in particular, in the perivascular fat), kidneys, heart, and brain promote a chronic inflammatory response that disrupts the blood pressure-regulating functions of these organs, leading to hypertension [56]. Accordingly, inflammation and immune system activation cause derangement in kidneys, arteries, brain, and heart functions that consequently promote hypertension and end-organ damage [57].

In support of the above mentioned hypothesis, current studies indicated that known stimuli that raise blood pressure (such as high-salt diet, Ang II, and DOCAsalt) directly and indirectly activate immune system cells. Elevated blood pressure can stress tissue cells to the level that DAMPs released by tissues. Moreover, hypertensive stimuli can directly activate immune cells and also cause formation of neoantigens in the tissues. As a result of released DAMPs, neoantigens, and direct immune cells activation by hypertension stimuli, activated immune cells are formed, target organs infiltrated by activated immune cells, and diverse inflammatory cytokines are released by the activated immune cells. Eventually, the affected target organs, mainly the kidney, blood vessels, and sympathetic nervous system function

*Immune System and Inflammation in Hypertension DOI: http://dx.doi.org/10.5772/intechopen.105203*

are perturbed and this leads to further elevated blood pressure level and finally to hypertension. Immune cells such as monocytes, macrophages, and dendritic cells (DCs) release pro-hypertensive cytokines that promote the BP elevation via actions in the vasculature (augmenting vascular dysfunction), kidney (increasing sodium retention), and stimulating sympathetic nervous system outflow [58].

Many studies implicated that in the kidney, inflammatory cells and their products contribute to blood pressure elevation at least in part by increasing renal sodium transport [59].

Genetic deletion of IL-6 in mice results in blunted hypertension in response to angiotensin II infusion [60]. Treating cortical collecting duct cells culture with IL-6 (100 ng/ml) for 12 h caused increased expression and activity of the epithelial sodium channel (ENaC) [61]. Mutations in ENaC that increase sodium reabsorption lead to the development of high blood pressure in Liddle's syndrome (a rare inherited form of hypertension) while mutations that inactivate ENaC have also been identified in humans, and these mutations lead to low blood pressure [62]. Taken together, these studies suggest that IL-6 enhances renal tubule sodium reabsorption and elevates BP at least in part through up regulation of renal tubule ENaC.

IL-1 is a pro-inflammatory cytokine that plays a central role in both acute and chronic inflammation, acting as a primary inducer of the innate immune response. Studies indicated that type 1 IL-1 receptor (IL-1R1) stimulation by IL-1 potentiates blood pressure elevation by suppressing nitric oxide (NO)-dependent sodium excretion in the kidney. Nitric oxide is a potent driver of sodium excretion in the kidney that acts via cyclic guanosine monophosphate (cGMP) and phosphodiesterase two to limit Na-K-2Cl cotransporter (NKCC2) activity in the medullary thick ascending limb. Thus, by relieving NO inhibitory effect on NKCC2, IL-1 enhances reabsorption of electrolytes by medullary thick ascending limb and enhances retention of sodium and water by kidney [39].

Interferon gamma (IFN-γ) is a proinflammatory cytokine produced by innate and adaptive immune cells, and T cell production of IFN-γ is increased in Ang II-induced hypertension and mice deficient in IFN-γ have a blunted blood pressure response to Ang II infusion. Experimental studies indicate that IFN-γ positively regulates sodium hydrogen exchanger 3 (NHE3) in the proximal tubule, NKCC2 in medullary thick ascending limb, and NCC in the distal tubule. Whether IFN-γ directly modulates these sodium transporters or acts through downstream mediators is unknown [62].

Interleukin 17A (IL-17A) is a pro-inflammatory cytokine produced predominantly by CD4+ T helper 17 (Th17) cells as well as gamma delta T cells. An experimental study that investigated effect of a proinflammatory cytokine interleukin 17 (IL17) reported that initial hypertensive response was similar for wild type mice (C57BL/6J mice) and interleukin 17 deficient mice (IL17−/− mice) however hypertension was not sustained in IL17−/− mice in Ang II hypertension model [40]. Mice model experimental studies and cell culture model studies showed that interleukin 17A up regulates NHE3 (in proximal segment), NCC and ENaC (in distal segment) of renal tubules. Moreover, studies implicated that interleukin 17A regulates renal sodium transporters through a serum and glucocorticoid regulated kinase 1 (SGK1) dependent pathway [63]. Serum and glucocorticoid regulated kinase1 is an important mediator of salt and water retention in the kidney through inhibition of neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2) mediated ubiquitination and degradation of NHE3, NCC, and ENaC in the renal tubule, thereby enhancing the expression of these transporters on the cell surface [64].

Besides its effect on electrolyte and water homeostasis regulation function of kidney, sustained inflammation results in renal fibrosis, oxidative stress, glomerular injury, and chronic kidney disease [59].

Blood vessels are other organs that are affected by activated immune system and chronic low grade inflammation associated with hypertension. Elevated blood pressure has an impact on the vasculature as a consequence of both the mechanical effects of blood pressure and shear stress [65]. Inflammation can impair blood vessels in two ways. Inflammation can cause functional arterial stiffening by impairing the functional relaxation capability of arteries. The other mechanism is structural remodeling of arteries due to hypertension-associated inflammation [66]. Likewise, many experimental studies confirmed involvement of immune cells and inflammatory cytokines in vascular dysfunction associated with experimental hypertension.

An experimental study done on mice showed that Ang II infusion in mice increased immune cell content (T cells, macrophages, and dendritic cells) in perivascular adipose tissue and adventitia [67].

Endothelial cell culture study showed that inflammatory marker, C-reactive protein (CRP), caused a marked down regulation of endothelial nitric oxide synthase (eNOS) mRNA and protein expression [68]. Similarly, TNF-α mediated inhibition of eNOS expression was observed in endothelial cell culture [69]. Acute treatment of endothelial cells with IL-17 caused a significant increase in phosphorylation of the inhibitory eNOS residue threonine 495 (eNOS Thr495) [70]. All these studies indicate that inflammation decreases bioavailability of endothelial NO and thus impairs vascular smooth muscle relaxation and subsequent vasodilatations.

Moreover, involvement of immune cells and inflammatory cytokines in hypertensive vascular remodeling is implicated by many studies. Reduced vascular remodeling showed in Ang II or DOCA- salt induced hypertension in osteopetrosis (Op/Op) mice [10]. In RAG1−/− mice (mice deficient in T and B lymphocytes) reduced aortic and small artery remodeling observed in response to Ang II-induced hypertension [41]. Similarly, interleukin 17A deficient (IL-17a−/−) mice are protected against aortic collagen deposition and aortic stiffening in response to chronic angiotensin II infusion [71]. These studies implicated that immune cells and inflammatory cytokines play roles in vascular fibrosis, remodeling of small and large vessels, and vascular rarefaction in hypertension. Nonetheless, this remains to be further investigated.

Other important organ both in development of hypertension and as an end-organ target of hypertension is the brain. Regulation of short-term blood pressure level by sympathetic nervous system (SNS) is well established. SNS stimulation is associated with constriction of blood vessels, increased cardiac output, and augmented sodium and fluid retention by the kidneys [72]. Moreover, SNS serves as an integrative interface between the brain and the immune system.

Mounting evidence implicate that many forms of essential hypertension are initiated and maintained by an elevated sympathetic tone [73]. The elevated sympathetic activity can be initiated by several factors including humoral factors such as angiotensin II and by environmental factors such as stress and high salt intake. In view of sympathetic nervous system substantial innervation to both primary (thymus, bone marrow) and secondary (spleen, lymph nodes, Peyer's patches) lymphoid tissues, and the central nervous system (CNS) powerful influences on the immune system and vice versa, it is reasonable to suppose that CNS enhance immune responses that lead to hypertension [74]. Pro-inflammatory cytokines (such as TNF-α, IL-1β) produced in the periphery can signal to the brain, passing through the BBB at points

#### *Immune System and Inflammation in Hypertension DOI: http://dx.doi.org/10.5772/intechopen.105203*

of increased permeability in the circumventricular organs (CVOs) and/or through disrupted blood brain barrier (BBB), and results in increased sympathetic outflow [75].

Observations such as increased splenic sympathetic nerve discharge (SND) and consequent increase in splenic cytokine gene expression (IL-1β, IL-6, IL-2, and IL-16) due to central Ang II administration (the effect which was abrogated by splenic sympathetic denervation), and others led to the hypothesis that central stimuli such as angiotensin II cause modest elevations of blood pressure, which leads to activation of immune system. Subsequently, the activated immune system leads to severe hypertension [76]. This hypothesis proposed a mechanism that occurs in a two-phase feed forward fashion. The initial phase brings a modest elevation in blood pressure (i.e. pre-hypertension), giving rise to an inflammatory response, possibly by generating "neoantigens" that activate innate and adaptive immune system. In the second phase, the activated immune system generates cytokines and other inflammatory mediators which work in concert with the direct effects of hypertensive stimuli (such as angiotensin II, catecholamines, and salt) to cause vascular and renal dysfunction, promote vasoconstriction, vascular remodeling, a shift in the pressure-natriuresis curve and sodium retention, and ultimately causes sustained hypertension [74].

#### **3. Conclusion**

Hypertension is a widely prevalent public health problem of world adult population. It is a major risk factor of cardiovascular diseases, chronic kidney disease, and dementia. Despite the availability of a plethora of hypertensive drugs, up to 40% of patients with hypertension fail to achieve adequate blood pressure control, even when prescribed a combination of drugs from three or more classes. This indicates lack of efficacy of existing hypertension treatment strategies and existence of additional drivers of hypertension that must be identified and may be targeted.

One of the proposed pathophysiologic mechanisms that contribute for elevated BP and target organ damage among hypertensive patients is activation of the immune system and chronic low grade systemic inflammation.

In kidneys, inflammatory cells and their products contribute to blood pressure elevation by increasing renal sodium retention and by causing renal fibrosis, oxidative stress, and glomerular injury. IL-1, IL-6, IFN-γ, and IL-17 are among pro-inflammatory cytokines that enhance sodium retention by renal tubules.

Activated immune cells and pro-inflammatory cytokines may contribute to functional arterial stiffening and structural remodeling of arteries that consequently cause elevated blood pressure in hypertension. C-reactive protein, TNF-α, and IL-17 may hamper synthesis of or inhibit nitric oxide (NO) synthase. Inflammatory cells that infiltrate blood vessels such as macrophages and lymphocytes and their proinflammatory products may also contribute for vascular remodeling.

Perturbed immune system and chronic low grade systemic inflammation also enhance SNS activity which in turn contributes to elevated blood pressure by its effect on blood vessels tone (vasoconstriction), on the kidneys (sodium and water retention, RAAS activation) and on immune system (activation of immune system and enhanced production pro-inflammatory cytokines).

Thus, unraveling the detail pathophysiological mechanisms by which activated immune system and inflammation contribute to hypertension paves a way to identify target, and to design and develop therapeutic intervention for hypertension.

Even though currently there is no anti-inflammatory drug to treat hypertension, anti-inflammatory agents that target specific inflammatory pathway (without compromising general immune system of an individual) are possible future hypertension treatment drugs.
