Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension

Abstract

Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.

Keywords: innate immunity; vascular dysfunction; vascular remodeling.

Fig. 1.

Paradoxical effects of Toll-like receptor (TLR) activation on vascular function. Short-term perturbations in the vasculature from either damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) activate TLRs present on innate immune system cells such as phagocytes, polymorphonuclear leukocytes, and natural killer cells, as well as somatic cells of the vasculature [vascular smooth muscle cells (VSMCs) and endothelial cells (ECs)]. This short-term interaction initiates an inflammatory response to restore homeostasis. However, chronic and/or excess activation of these receptors due to the continuous presence of DAMPs from cell death and remodeling negates the beneficial effects of these receptors and contributes to a pro-inflammatory state and blood pressure elevation.

Fig. 2.

The collective contribution of the innate and adaptive immune systems to vascular dysfunction, vascular remodeling, and hypertension. After an initial reflexive spike due to the presence of DAMPs in the circulation (e.g., those that may arise due to prehypertensive stimuli such as ANG II, high salt, or chronic stress), the innate immune system resets to new level of homeostasis due to the ever increasing levels of DAMPs in the circulation from continued pressure- and ischemic-induced cell death and remodeling. The adaptive immune system responds accordingly, reacting to the inflammatory stimuli initiated by the innate immune system. Because TLRs and other innate and adaptive immune system effectors remain in a state of sustained activation henceforth, chronic inflammation ensues, and blood pressure rises in concert with other dysregulated systems (e.g., increased sympathetic drive and decreased renal function).

Fig. 3.

TLR ligands/DAMPs, cellular location, and signaling in the vasculature. Evolutionarily conserved similarities between TLRs on immune cells have been extended to somatic cells of the vasculature (i.e., VSMCs and ECs). TLR1, TLR2, TLR4, TLR5, and TLR6 are expressed on the plasma membrane, and TLR3, TLR7, TLR8, and TLR9 are expressed on endosomal vacuoles. Activation of these receptors by DAMPs and PAMPs leads to complex cellular signaling cascades mediated by myeloid differentiation primary response protein (MyD88), Toll-IL-1 receptor (TIR)-domain-containing adaptor inducing interferon β (TRIF), TIR domain-containing adaptor protein (TIRAP), and TRIF-related adaptor molecule (TRAM). These adaptor molecules signal via MyD88-dependent or MyD88-independent pathways that result in the upregulation of pro-inflammatory mediators (cytokines, chemokines, and adhesion molecules). The MyD88-dependent pathway includes NF-κB translocation to the nucleus to regulate inflammatory gene expression. TLR signaling activates the endogenous NF-κB inhibitor IKK complex, which phosphorylates IκB and leads to its ubiquitylation and degradation by the proteasome. IκB degradation relieves the inhibitory influence on NF-κB, and NF-κB is then able to translocate from the cytoplasm into the nucleus. MAPK regulation of pro-inflammatory mediators is also MyD88 dependent. The MAPK module contains at least 3 protein kinases in series that culminate in the activation of a multifunctional MAPK (ERK1/2, JNK/SAPK, and p38). These MAPKs subsequently result in the activation of the transcription factor activator protein (AP-1), which then translocates to the nucleus. Interferon regulatory factor (IRF)7 is also MyD88 dependent, but is only found downstream of TLR9. Phosphorylation and dimerization of IRF7 activate its translocation to the nucleus. The MyD88-independent(/TRIF-dependent) pathway downstream of TLR3 and TLR4 involves IRF3, as well as NF-κB activation. Like IRF7, IRF3 undergoes phosphorylation and dimerization for activation and translocation to the nucleus. dsRNA, double-stranded RNA; HSP, heat shock protein; mHDL, (pathophysiologically) modified HDL; ssRNA, single stranded RNA.

Fig. 4.

Schematic demonstrating the novel hypothesis that circulating mitochondrial DNA (mtDNA), released following cell injury from modest elevations in total peripheral resistance, leads to TLR9 activation in VSMCs, ECs, and immune cells (e.g., monocytes and macrophages). This can subsequently activate a positive feedback loop, exacerbating further cell injury and/or death and promoting vascular remodeling and hypertension.