Immunity and hypertension: New targets to lighten the pressure

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This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc

Hypertension is defined as a persistent elevation in BP—more specifically, ≥140‐mmHg systolic and 90‐mmHg diastolic pressure (Whelton et al., 2018). According to a recent systematic analysis, hypertension was ranked as the leading risk factor for the global burden of disease, outweighing genetic, occupational, lifestyle, and environmental factors (GBD 2015 Risk Factors Collaborators, 2016). Current anti‐hypertensive therapies are aimed at controlling the classical physiological systems that regulate BP including the renin angiotensin‐aldosterone system (RAAS) or sympathetic nervous system. Surprisingly, these therapies fail in ~40% of cases and yet a new class of anti‐hypertensive drugs has not been developed for the past 20 years. There is clearly a need to further understand the pathophysiology of hypertension so as to develop novel therapeutic approaches to control BP. Since 2007, there has been renewed interest in how the immune system and inflammation influence the development of hypertension. Indeed, over the past decade, several paradigm‐shifting contributions have supported the possibility of targeting the immune system to control hypertension through the development of novel targeted therapies or the repurposing of current immunomodulatory agents commonly used to control autoimmune/inflammatory disorders (Drummond, Vinh, Guzik & Sobey, 2019). This themed section is a collection of original research papers that contribute further to this field of research, as well as comprehensive review articles that document the exciting discoveries that link several aspects of immunity with the control of BP.

Much research in the field of immunity, inflammation, and hypertension in the past decade has focused on the multiple aspects of a classical immune response. These include (a) the stimulus involved in immune activation; (b) the particular immune cells and mediators (e.g., cytokines and chemokines) that contribute to the immune response; and (c) the targets of the immune response during hypertension (systemic versus tissues/organs). Many studies have adopted experimental approaches based on the seminal study by Harrison and colleagues, which showed recombinase activating gene‐1‐deficient (Rag1^−/−) mice—that lack T and B cells—to exhibit blunted responses to hypertensive stimuli (Guzik et al., 2007). These observations have been well supported by subsequent studies in other strains of immunodeficient mice (Crowley et al., 2010) and rats (Mattson et al., 2013). Based on current knowledge, an overarching hypothesis has been proposed whereby hypertension is associated with activation of the immune system that then leads to the recruitment and accumulation of immune cells (especially lymphocytes and macrophages) within BP‐controlling organs, such as the vasculature and kidneys. These immune infiltrates then promote local inflammation and fibrosis that ultimately causes organ damage and poor control of BP. These concepts are summarised in a review article in this issue by Caillon, Paradis, and Schiffrin (2019).

Classically, the immune system is activated in response to foreign or “non‐self” molecules recognised as such by innate immune cells such as macrophages and dendritic cells. The innate response is a first line of defence that is considered non‐specific, and the cells that comprise this arm of the immune system typically engulf and either directly kill the pathogen, or digest it and present a pathogen‐specific antigen to cells of the adaptive immune system, which include T and B cells. This presentation of disease‐specific antigens leads to activation of the adaptive immune system and the generation of antigen‐experienced or effector T and B cells that mount a powerful and highly specific immune response to destroy the pathogen. A large focus in the field of immunity and hypertension research has been to ascertain whether a classical immune response—such as that outlined above—is involved in the development of hypertension. Indeed, previous studies have shown that T cell activation during hypertension requires classical antigen presentation (Vinh et al., 2010), with a major implication of this discovery being the likelihood of hypertension‐specific “neoantigens” generated and presented to T cells. Recent studies have implicated isolevuglandin‐modified proteins as potential candidates for the hypertension‐specific neoantigen (Barbaro et al., 2017; Kirabo et al., 2014). However, a large body of evidence has also highlighted heat shock protein 70 (HSP70)—a chaperone protein—as an immunogenic antigen in experimental and clinical hypertension. Rodriguez‐Iturbe, Lanaspa, and Johnson (2019) were instrumental in ascribing a role for HSP70 in adaptive immunity during hypertension, and in this issue they provide an update on recent findings in this area.

The mechanisms by which hypertension‐specific neoantigens are generated remains a topic of discussion. The current narrative describes the generation of neoantigens following an initial elevation in BP in response to physiological stressors, including the RAAS, SNS, and oxidative stress (Harrison, Vinh, Lob, & Madhur, 2010). For example, preventing elevations in BP in the presence of experimental stimuli for hypertension also prevents the development of peripheral and vascular inflammation (Marvar et al., 2010). The mechanisms by which the SNS controls the immune system and hypertension are comprehensively reviewed by Carnagarin, Matthews, Zaldivia, Peter, and Schlaich (2019). How elevations in pressure directly lead to neoantigen formation and activation of the immune system remains unclear; however, there is now evidence that changes in the local environment associated with sodium imbalance can directly regulate inflammation. Seminal work by Machnik et al. (2010) highlighted that the innate immune system is sensitive to changes in salt levels and acts to regulate interstitial sodium clearance to reduce BP. Elevations in salt also directly promote T cell‐mediated autoimmune disease via the release of the pro‐inflammatory cytokine IL‐17. More recently, high salt has been shown to increase the generation of isolevuglandins, which can directly activate the adaptive immune system (Barbaro et al., 2017). The role of salt and inflammation in the setting of hypertension—with a focus on the cytokine, IL‐17—is reviewed by Wenzel, Bode, Kurts, and Ehmke (2019).

The innate immune system has also garnered much interest in this research field. As mentioned, the local micro‐environment can be regulated by the innate immune system. Conversely, increases in salt have been associated with activation of the innate immune system via the multiprotein intracellular complex called the inflammasome. The inflammasome is sensitive to pathogenic microorganisms but also noxious environmental sterile stressors that are detected via pattern recognition receptors (PRRs) such as toll like receptors (TLRs); the role of TLR4 in hypertension is comprehensively reviewed by Nunes, de Oliveira, Mowry, and Biancardi (2019) in this issue. This event ultimately results in assembly of an oligomeric complex, leading to the release of the cytokines IL‐1β and IL‐18, that then act on their own receptors to mount a potent inflammatory response (Krishnan et al., 2016; Latz, 2010). Recently, Krishnan et al. (2016) showed that the NLRP3 inflammasome is essential for hypertension induced by 1 kidney‐deoxycorticosterone with high salt. Pharmacological inhibition of the NLRP3 inflammasome reverses experimental hypertension and associated renal inflammation (Krishnan et al., 2019). In this issue, Scott, Kemp‐Harper, and Hobbs (2019) cover an emerging topic discussing how the pro‐inflammatory role of the inflammasome also extends to pulmonary hypertension and may represent a therapeutic target.

Hypertension and cardiovascular disease have been long associated with other co‐morbidities including rheumatoid arthritis and systemic lupus erythematosus (SLE). While the mechanistic links were originally unclear beyond the basic understanding that secondary hypertension occurred as a result of organ damage (e.g., SLE and renal dysfunction), the identification of an important role for the immune system in hypertension has made an inflammatory link somewhat clearer. It is currently thought that heightened immune responses during autoimmune disease can influence the pro‐inflammatory response during hypertension leading to augmentation of the pathology. Taylor, Wolf, Dent, and Ryan (2019) review the current evidence linking rheumatic diseases and hypertension, with a focus on the contribution of (auto)antibodies to the pathogenesis of inflammation associated with hypertension. Antibodies play a part in the humoral immune response and are produced by B cells of the adaptive immune system. Autoantibodies have been detected in the setting of the hypertension associated with preeclampsia and have been shown to exhibit agonistic properties at receptors classically associated with activation of the RAAS (angiotensin AT₁ receptor; LaMarca et al., 2009) and SNS (α‐adrenoceptors; Luther, Homuth, & Wallukat, 1997). In this issue, Cornelius, Cottrell, Amaral, and LaMarca (2019) discuss the current links between immune mediators and preeclampsia.

In addition to autoimmune diseases, hypertension has also been linked to other chronic conditions including infection and stress. Czesnikiewicz‐Guzik et al. (2019) present new data showing that oral gum infection by Porphyromonas gingavalis induces a Th1‐mediated response (increased IFN‐γ production) that can augment hypertension. Stress has also been linked to elevated immune activation and subsequent hypertension in animal models of hypertension (Marvar et al., 2012). Obi, McPherson, and Pollock (2019) review the mechanistic links between adverse childhood experiences, including traumatic events in humans and early life stressors in mice and rats, to vasoactive factors and immune mediators associated with cardiovascular disease and risk of hypertension.

While we have discussed potential stimuli for activation of the immune system and current co‐morbidities and associations between inflammation and hypertension, an important underlying question remains: how does the immune system directly promote hypertension? This is indeed an extremely important question, and one that is proving difficult to answer. We are only beginning to unravel the multitude of mechanisms by which the immune system can influence the regulation of BP. One key aspect of immunity and hypertension research that dates back to the 1960s is the recruitment and accumulation of immune cells into BP‐controlling organs such as the blood vessels and kidneys. Conventionally, immune cells are recruited to peripheral sites via chemokines—chemotactic cytokines—that bind to chemokine receptors expressed on surfaces of immune cells. There are multiple families of chemokines and receptors, and initial studies have highlighted roles for the CCL5/CCR5 (Guzik et al., 2007; Mikolajczyk et al., 2016) and CCL2/CCR2 (Chan et al., 2012; Moore et al., 2015) chemokine pathways in aortic infiltration of T cells and monocytes/macrophages during hypertension. With respect to the latter pathway, Mikolajczyk et al. (2019) present original data in this issue showing that plant‐derived molecules that suppress CCL2 expression can prevent accumulation of immune cells in the aortic perivascular adipose tissue, and subsequently blunt the development of hypertension. Understanding the trafficking of immune cells during hypertension may be important for the development of therapies to control their accumulation in BP‐controlling organs so as to mitigate their local pro‐inflammatory actions. Wenzel (2019) summarises how monocytes traffic into the vascular wall and explores whether targeting monocytes with various pharmacological approaches may be a possible therapeutic option to control local inflammation of BP‐controlling organs. Balasubbramanian, Lopez Gelston, Rutkowski, and Mitchell (2019) describe the current evidence for lymphatics as highways for trafficking of T cells and other immune cells in hypertension. Another pleiotropic molecule involved in immunoregulation including trafficking/migration is sphingosine‐1‐phosphate (S1P). S1P can influence trafficking, proliferation and survival of immune cells and its influence on immune cell trafficking in the setting of hypertension is thoroughly summarised by Don‐Doncow, Zhang, Matuskova, and Meissner (2019).

While mechanisms of recruitment of immune cells represent potential pharmacological targets, much research has focused on pro‐inflammatory mediators that immune cells release into the local environment. Since the initial studies implicating T cells in hypertension (Guzik et al., 2007), there has been a focus on the role of T helper (Th) cell phenotypes and the cytokines they produce. Th cells can be broadly categorised by the specific cytokines they release [e.g., Th1 (IFN‐γ), Th2 (IL‐4), and Th17 (IL‐17)], which is well described in the review by Caillon et al. (2019). Several studies have reported that IFN‐γ (Kamat et al., 2015; Saleh et al., 2015) contributes to the development of hypertension. Important work by the Madhur group strongly supports IL‐17 as a therapeutic target to control inflammation associated with hypertension (Madhur et al., 2010; Norlander et al., 2016; Saleh, Norlander, & Madhur, 2016). Interestingly, new data from Rosendahl et al. (2019) contrast with current evidence and suggest that IL‐17A is not involved in the 5/6 nephrectomy model of chronic kidney disease. Another recent study also reports that IL‐17A‐deficiency does not protect against ischaemia–reperfusion injury‐induced fibrosis (Thorenz et al., 2017). While hypertension is commonly associated with renal dysfunction and fibrosis, collectively, these studies highlight a complex interplay between local immune mechanisms that may be specific for different models of the disease. Importantly, gaining a deeper understanding of the specific mechanisms involved in “immune‐mediated” hypertension will likely facilitate more selective therapies to be translated to the clinic, as opposed to broad spectrum immunosuppressants.

The application of immunomodulatory therapies to treat autoimmune/inflammatory disorders has been established for decades. The ultimate question that remains to be determined is whether we can target the immune system in clinical hypertension. There is an expanding body of evidence indicating that experimental hypertension is associated with the immune system and inflammation, but only a limited number of clinical studies have so far reported these associations to also occur in human hypertension. Interestingly, one of the earliest studies linking aberrant immune function with clinical hypertension was published in 1970, where Ebringer and Doyle (1970) showed elevated serum antibody levels in patients with hypertension. More recently, increased levels of CD8+ T cells with an activated phenotype were detected in hypertensive patients (Youn et al., 2013). Genome‐wide association studies have reported gene expression profiles in hypertension that are strongly linked to immunity and inflammation (Huan et al., 2015). Alexander et al. (2019) present strong associations between elevated IL‐18RAP, an accessory protein required for IL‐18 signalling via the IL‐18 receptor, and hypertension in patients. As discussed earlier, the principal pathway for IL‐18 production is via the inflammasome which has been reported to play an important role in experimental hypertension (Krishnan et al., 2016; Krishnan, Sobey, Latz, Mansell, & Drummond, 2014). Thus, strong links between clinical and experimental hypertension are emerging, and one of the key questions to be answered is whether the benefits of suppressing organ/systemic inflammation and ultimately hypertension outweigh the risks of immunosuppression. Bomfim, Cau, Bruno, Fedoce, and Carneiro (2019) summarise current knowledge on the use of immunomodulatory therapies in experimental and clinical hypertension and consider whether there is merit to their application as a novel therapeutic approach to control BP.

Hypertension is the leading biomedical risk factor for the global burden of disease (GBD 2015 Risk Factors Collaborators, 2016). There is an accumulating body of evidence to support a role for immunity and inflammation in hypertension, much of which has been summarised and reviewed in this themed section on Immune Targets in Hypertension. A last thought to consider here is that the latest SPRINT trial reported a 9.8% incidence of serious adverse events seen with conventional anti‐hypertensive medications in patients with primary hypertension (Wright et al., 2015). Two recent studies using methotrexate in patients with rheumatoid arthritis reported a withdrawal rate of a comparable proportion of patients (~12.8% due to adverse events; Kinder et al., 2005; Varatharajan et al., 2009). With many well‐tolerated immunomodulatory therapies available, we suggest that it is perhaps now time to consider whether such drugs could soon be used alone or as adjunct therapies to control hypertension.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Vinh A, Drummond GR, Sobey CG. Immunity and hypertension: New targets to lighten the pressure. Br J Pharmacol. 2019;176:1813–1817. 10.1111/bph.14659