Abstract
Inflammatory mediators play a critical role in the regulation of sympathetic outflow to cardiovascular organs in hypertension. Emerging evidence highlights the involvement of immune cells in the regulation of blood pressure. However, it is still unclear how these immune cells are activated and recruited to key autonomic brain regions to regulate sympathetic outflow to cardiovascular organs. Chemokines such as C-C motif chemokine ligand 2 (CCL2), and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), are upregulated both peripherally and centrally in hypertension. More specifically, they are upregulated in key autonomic brain regions that control sympathetic activity and blood pressure such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. Furthermore, this upregulation of inflammatory mediators is associated with the infiltration of immune cells to these brain areas. Thus, expression of pro-inflammatory chemokines and cytokines is a potential mechanism promoting invasion of immune cells into key autonomic brain regions. In pathophysiological conditions, this can result in abnormal activation of brain circuits that control sympathetic nerve activity to cardiovascular organs and ultimately in increases in blood pressure. In this review, we discuss emerging evidence that helps explain how immune cells are chemoattracted to autonomic nuclei and contribute to changes in sympathetic outflow and blood pressure.
Highlights
The autonomic nervous system plays a major role in blood pressure regulation whereby dysfunction can lead to hypertension
Immune Involvement in Neurogenic Hypertension the regulation of sympathetic outflow to cardiovascular organs via direct projections to sympathetic preganglionic neurons (SPNs) located in the spinal cord (Strack et al, 1989a,b; Schramm et al, 1993). These brain regions play an important role in regulating homeostatic levels of sympathetic outflow to the cardiovascular organs such that activation of the area postrema (AP), by inflammatory mediators such as tumor necrosis factor alpha (TNF-α), for example, can lead to increases in both cardiac and renal sympathetic nerve activity (Korim et al, 2018)
While the blood-brain barrier (BBB) prevents immune cells from entering the brain, we have previously suggested that this structure is disrupted in hypertension (Setiadi et al, 2018)
Summary
The autonomic nervous system plays a major role in blood pressure regulation whereby dysfunction can lead to hypertension. Studies in experimental rodent models of hypertension confirm this finding They further show that upregulation of a wide range of pro-inflammatory mediators occurs in key brain regions known to regulate sympathetic outflow to cardiovascular organs (Shen et al, 2015). The increase in CCL2 levels in SHRs forms a gradient from the bone marrow (lowest concentrations) toward the cerebrospinal fluid (highest concentrations) (Santisteban et al, 2015), possibly forming a chemotactic gradient toward the central nervous system It seems that CCL2 chemoattracts immune cells and triggers an inflammatory cascade within the brain, leading to increases in BP. The application of CCL2 to primary human brain endothelial cell cultures induces the expression of cell adhesion molecules, such as PECAM-1 on the surface membrane of endothelial cells, which is required for facilitating transmigration of immune cells through endothelial cells
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