Toll-Like Receptors in Essential Hypertension: Comparison
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Please note this is a comparison between Version 1 by Antonios Lazaridis and Version 2 by Peter Tang.

Essential hypertension (EH) is a highly heterogenous disease with a complex etiology. Toll-like receptors (TLRs) have been implied as novel effectors in this inflammatory environment since they can significantly stimulate the production of pro-inflammatory cytokines, the migration and proliferation of smooth muscle cells and the generation of reactive oxygen species (ROS), facilitating a low-intensity inflammatory background that is evident from the very early stages of hypertension. Furthermore, the net result of their activation is oxidative stress, endothelial dysfunction, vascular remodeling, and finally, vascular target organ damage, which forms the pathogenetic basis of EH. Importantly, evidence of augmented TLR expression and activation in hypertension has been documented not only in immune but also in several non-immune cells located in the central nervous system, the kidneys, and the vasculature which form the pathogenetic core systems operating in hypertensive disease.

  • hypertension
  • innate immunity
  • toll-like receptors
  • inflammation
  • cytokines

1. Introduction

Essential hypertension (EH) has an independent and continuous relationship with the incidence of several cardiovascular events, and it is a leading cause of cardiovascular morbidity and mortality, surpassing all other cardiovascular risk factors such as diabetes mellitus, smoking, and hyperlipidemia [1][2]. In particular, the global burden of EH currently affects almost 30 to 45% of all adults and accounts for almost 10 million deaths and over 200 million disability-adjusted life years worldwide, with a constantly increasing tendency [3][4]. The continuous and close relationship of hypertension with cardiovascular disease, along with its overall prevalence worldwide, clearly render EH a major issue of public health that calls for immediate action.

Despite advances in awareness and pharmacotherapy, no unifying mechanism, and thus, no single therapeutic target exists, rendering control rates in the general hypertensive population unacceptably low. This is due to the fact that EH is a highly heterogenous disease with a multifactorial and complex etiology, still not fully elucidated [5]. Recently, chronic inflammation triggered and sustained by excessive immune system activation has been implicated as a novel contributor to the pathogenesis of the disease [6]. Towards this direction, accumulating evidence has highlighted the role of toll-like receptors (TLRs) as major effectors of innate immunity, in promoting inflammation, oxidative stress, and endothelial dysfunction—all major pathophysiologic components mediating vascular damage in EH [7][8][9][10].

2. Pathogenesis of Hypertension

It has been strongly supported that the pathogenesis of EH mainly consists of a noxious interplay between sophisticated neural, vascular, renal, and hormonal mechanisms, of which increased activation of the sympathetic nervous (SNS) and the renin-angiotensin system (RAS) prevail [5]. However, in recent years, it has been advocated that the core pathophysiologic event behind most of these mechanisms operating at the biological level is inflammation [11]. More specifically, a growing amount of evidence has demonstrated that multiple inflammatory mechanisms including pro-inflammatory cytokine and chemokine expression, cell infiltration and oxidative stress—all triggered and sustained by excessive immune system activation—are highly upregulated in the hypertensive environment [6][12].

3. The Role of the Immune System in the Pathogenesis of Hypertension

The immune system consists of both innate and adaptive immunity. Innate immunity represents the first line of defense of the human body and its main effector cells include dendritic cells, macrophages, granulocytes, natural killer (NK) cells, B cells, and mast cells, all of which act rapidly and non-specifically once activated by the presenting antigens. In contrast, adaptive immunity consists of T and B lymphocytes that mainly depend upon antigen recognition by the antigen-presenting cells in order to elicit a more robust inflammatory response [13].

Both systems are actively implicated in the pathogenesis of EH. More specifically, it has been hypothesized that hypertensive stimuli including angiotensin II (AngII), aldosterone, endothelin-1, salt, and several genes (i.e., ADRA2A [10q24-q26] (which is the predominant subtype gene modulating SNS outflow in the brain), ADRA2C [4p16.1], and ADRA2B [2p13-q13]) [14][15] increase central nervous signaling and thus SNS activity, which, in turn, provokes slight elevations in blood pressure (BP) [11]. This initial event leads to tissue injury and the release of endogenous intra- or extracellular molecules including cell-derived nucleic acids, fatty acids, heat shock proteins (HSPs), and high-mobility group box-1 (HMGB1), all termed damage-associated molecular patterns (DAMPs). Under normal conditions, DAMPs represent an acute “alarm signal”, warning the host to activate its defense mechanisms of which innate immunity is the first and most crucial one. In the hypertensive environment, though, it has been hypothesized that the pronounced DAMP-mediated stimulation of the immune system leads to significant inflammatory responses through two distinct pathways: i) the direct stimulation of innate immune cells further activating deleterious mechanisms including organ infiltration, chemokine and pro-inflammatory cytokine production, oxidative stress, phagocytosis, and complement activation, or ii) the consequent activation of adaptive immunity [6]. Activation of the adaptive immune response leads to the polarization of naive CD4+ T helper lymphocytes (Th0) towards pro-inflammatory T helper Th1 and Th17 phenotypes that produce reactive oxygen species (ROS), interferon (IFN)-γ, and interleukin (IL)-17 [16]. The net effect is a state of chronic low-grade inflammation that leads to additional vascular dysfunction, increased BP, tissue injury, and finally, the release of more DAMPs, which, in turn, flare up and maintain immune system hyperresponsiveness [17]. As a result, a vicious cycle of immune system activation and aberrant vascular inflammation is installed, ending up in target-organ damage and the further progression of EH [12] (Figure 1).

Ijms 22 03451 g001 550
Figure 1. Schematic representation of the mechanisms of innate immunity implicated in the pathogenesis of hypertension. Endogenous stimuli including angiotensin II (AngII), aldosterone, endothelin-1, salt, and several genes initially increase central nervous signaling and thus sympathetic nervous system (SNS) activity, which, in turn, provokes a slight elevation in blood pressure (BP). This event leads to tissue injury and the release of endogenous intra- or extracellular molecules including cell-derived nucleic acids, fatty acids, heat shock proteins (HSPs), and high-mobility group box-1 (HMGB1), all termed damage-associated molecular patterns (DAMPs). In the hypertensive environment, an excessive or prolonged DAMP-mediated stimulation of innate immunity leads to an aberrant immunologic response through the activation of toll-like receptors (TLRs). The result is chronic low-grade inflammation, oxidative stress, and endothelial dysfunction, all of which inflict damage on the kidneys and the vascular system, thus further increasing BP. Importantly, increased TLR expression and subsequent activation has been documented not only on immune but also on non-immune cells of the central nervous, renal, and vascular system, all major contributors in the pathogenesis of hypertension.

Whereas data support the participation of adaptive immunity in the pathogenesis of hypertension [16][18], the extent of the involvement of innate immunity, the precise mechanisms that stimulate it as well as its subsequent firing effects on adaptive immunity are still not well understood. To this end, the key role of TLRs in stimulating innate immunity and promoting inflammation in the hypertensive environment, merits further investigation.

4. Toll-Like Receptors

TLRs are type I transmembrane proteins belonging to the class of pattern recognition receptors (PRRs). In general, PRRs are in charge of recognizing and initiating an inflammatory reaction in response to unique, evolutionary conserved motifs termed either pathogen-associated molecular patterns (PAMPs), which are produced from viral and bacterial products, or DAMPs, which are released in the context of tissue damage, cellular stress, or cell death [10][19]. To date, 10 TLR subtypes have been identified in humans [TLR (1–10)] classified into two subfamilies according to their localization—the cell surface TLRs (1, 2, 4–6), expressed on the cell surface, and the intracellular TLRs (3, 7–10), localized in the endosomal compartment [10].

TLRs constitute the primary and most crucial step in the initiation of the inflammatory response by innate immunity. Upon activation by a specific PAMP or DAMP, TLRs fire an intracellular signal transduction cascade through two different pathways, namely (i) the myeloid differentiation primary response protein 88 (MyD88)-dependent pathway, which induces the activation of the early phase nuclear factor-κB (NF-κB), and (ii) the myD88-independent pathway (Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-b [TRIF] dependent), which induces the activation of the late phase NF-κB. Both pathways culminate in the production and release of proinflammatory cytokines, chemokines, and several co-stimulatory factors all of which facilitate the inflammatory response [10][20][21]. In the hypertensive environment, TLRs are subject to excessive or prolonged DAMP-mediated stimulation that leads to an exaggerated innate immune inflammatory response and vascular damage.

5. The Role of Toll-Like Receptors in the Pathogenesis of Hypertension

A concise amount of data has demonstrated evidence of increased TLR activation leading to inflammation in hypertension [8][9][10][22]. Importantly, enhanced TLR expression has been documented not only on immune cells but also on several non-immune cells across the renal, vascular, and neural tissues, representing the three most vital target organs involved in the pathogenesis of EH (Table 1).

Table 1. Experimental populations where TLR activation has been documented and the relevant subtypes of TLRs involved in the pathogenesis of hypertension according to organ system.

Organ System

TLR Subtype

Experimental Populations

Central Nervous System

TLR4

TLR7

TLR8

TLR9

Normotension [23]

Pre-hypertensive SHRs

[24]

SHRs

[

25][26]

AngII-induced hypertension

[

27

][28]

Vascular System

TLR2

TLR4

TLR9

Normotension [29]

SHRs

[29][30][31][32]

AngII-induced hypertension

[

33]

L-NAME induced hypertension

[

34

]

Renal System

TLR4

AngII-induced hypertension [35]

Aldosterone-induced hypertension

[36]

AngII: angiotensin II; L-NAME: NG-nitro-L-arginine methyl ester; SHRs: spontaneously hypertensive rats; TLR: toll-like receptor.

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