Immune Mechanisms in Hypertension

Abstract

It is now apparent that immune mediators including complement, cytokines, and cells of the innate and adaptive immune system contribute not only to blood pressure elevation but also to the target organ damage that occurs in response to stimuli like high salt, aldosterone, angiotensin II, and sympathetic outflow. Alterations of vascular hemodynamic factors, including microvascular pulsatility and shear forces, lead to vascular release of mediators that affect myeloid cells to become potent antigen-presenting cells and promote T-cell activation. Research in the past 2 decades has defined specific biochemical and molecular pathways that are engaged by these stimuli and an emerging paradigm is these not only lead to immune activation, but that products of immune cells, including cytokines, reactive oxygen species, and metalloproteinases act on target cells to further raise blood pressure in a feed-forward fashion. In this review, we will discuss these molecular and pathophysiological events and discuss clinical interventions that might prove effective in quelling this inflammatory process in hypertension and related cardiovascular diseases.

Keywords: autoimmunity; cytokines; dendritic cells; inflammation; neuroimmune.

Figure 1:

Sources of tissue myeloid cells that have been shown to contribute to end-organ damage and dysfunction in hypertension. CCR2⁺ circulating monocytes are recruited to the interstitial space, where they can exist with minimal phenotypic change, or transform to macrophages or monocyte-derived dendritic cells.^, Created with BioRender.com and used with permission.

Figure 2:

Effect of hypertensive stretch on monocyte activation. In the setting of 5% cyclical stretch, endothelial cells release NO and likely other mediators that inhibit transformation of monocytes. In the setting of hypertensive (10%) cyclical stretch, endothelial cells produce less NO and increased amounts of IL-6 and hydrogen peroxide. This enhnaces the transformation of classical (CD14⁺) monocytes to an intermediate phenotype (CD14⁺/CD16⁺) that produce large amounts of IL-6, IL-23, TNFα, and IL-1β. These cells can also stimulate proliferation of T cells from the same subject. Adopted from Loperena et al. A subset of these transformed monocytes exhibit Axl and Siglec6, and seem to play a pro-hypertensive role, as shown in Figure 3. Created with BioRender.com and used with permission.

Figure 3:

Mechanisms of end organ damage and dysfunction caused by central artery stiffening. In various diseases, central artery stiffening increases pulse wave transmission into the microcirculation, leading to enhanced mechanical activation of the microvascular endothelium. This promotes release of growth arrest specific 6 (GAS6), activation of Axl on myeloid cells, and infiltation of immune cells into the vasculature and kidney. Modified from Chen et al. Created with BioRender.com and used with permission.

Figure 4:

Components of the immunological synapse known to be involved in hypertension. The T cell receptor (TCR) recognizes and binds to antigens presented in the context of major histocompatibility complexes (MHCs). Co-stimulation involving receptor ligand pairs such as CD28 and the B7 ligands (CD80 and CD86), or CD27 with CD70, are required for sustained T cell activation. Deletion of either the B7 ligands, or CD70, reduces hypertension. Inhibitory stimuli include the PD1/PDL1, and inhibition of these worsen hypertension. Created with BioRender.com and used with permission.

Figure 5:

Emerging role of isolevuglandins (IsoLGs) in hypertension and related cardiovascular diseases. IsoLGs are peroxidation products of arachidonic acid, and rapidly form covalent bonds with lysine residues on proteins. These are processed to peptides which are presented as neoantigens that activate T cells. IsoLGs can also disrupt histone assembly, leading to granulocyte DNA release and NETosis. By binding to lysines on critical transcription factors, such as PU.1, these disrupt transcriptional regulation of critical proteins, such as the complement factor C1q, promoting systemic lupus and the hypertension related to this disease. IsoLGs also can cause cross bridging of proteins in conditions like atrial fibrillation, commonly associated with hypertension. Created with BioRender.com and used with permission.

Figure 6:

Role of the immunoproteasome in processing IsoLG-modified proteins in both dendritic cells (DCs) and endothelial cells. While IsoLG-modified proteins inhibit the constitutive proteasome (Panel A), the immunoproteasome is increased and activated in hypertension, and avidly processes these altered proteins to IsoLG-peptide adducts. This occurs in DCs (Panel B), which in turn present these peptides to T cells. A similar process occurs in endothelial cells (Panel C), which can also activate T cells, and by presenting the same antigen as the DCs allow directed homing of T cells to specific tissues. From de la Visitación et al. Created with BioRender.com and used with permission.

Figure 7:

Neuroimmune interactions in hypertension. Panel A shows specific brain regions known to modulate sympathetic outflow and immune activation in hypertension. AV3v = anteroventricular 3rd ventricle, SFO = subfornical organ, OVLT = organum vasculosum of the lamina terminalis, RVLM = rostroventral lateral medulla. Lesions of these sites modulate immune activation in response to ang II or salt (in the case of the OVLT). Also shown are hypothalamic microglial cells that are activated in hypertension. Panel B shows splenic innervation and the unique origin of norepinephrine (norepinephrine) releasing nerves. Ach = acetylcholine. Chat = choline acetyltransferase. PlGF = placental like growth factor. Panel C shows effects of sympathetic stimulation on immune activation in the kidney and the action of NE on β2-AdR in the bone marrow to promote homing and survival of memory T cells. Created with BioRender.com and used with permission.