The Chemoattraction of Immune Cells into the Hypothalamic Paraventricular Nucleus Elicits Sympathetically‐Mediated Blood Pressure Elevations in Hypertension

Abstract

Chemokine C‐C motif ligand 2 (CCL2) is a chemotactic cytokine, known for its ability to recruit and activate immune cells. Recently, immune cells have been shown to be active within the paraventricular nucleus of the hypothalamus (PVN) of a rodent model of hypertension. Interestingly, the chemokine, CCL2, was increased by 3‐fold in the PVN in many experimental models of hypertension, and the plasma levels of CCL2 appear to correlate with increased blood pressure in hypertensive patients. However, the underlying neural and molecular mechanisms leading to the development of hypertension still remain unknown. Thus, we hypothesised that CCL2 elicits sympathetically mediated blood pressure (BP) elevations through the recruitment of immune cells into the PVN. Here, we show, in anaesthetised Sprague‐Dawley rats, activation of receptors for CCL2 (i.e. CCR2), in the PVN, recruits immune cells that infiltrate into the PVN from the peripheral circulation, eliciting dose‐dependent elevations in blood pressure and renal sympathetic nerve activity. Further, our results in conscious freely moving rats show that microinjection of CCL2 into the PVN, increased blood pressure by approximately 12±2 mmHg, and this increase lasted for 50 minutes. In renovascular hypertensive rats (2 kidney ‐ 1 clip), plasma and cerebrospinal fluid levels of CCL2 were elevated with the onset occurring in the first week, prior to the development of hypertension. Immune cell infiltration into the PVN was also evident by the second week, when animals were still pre‐hypertensive. Importantly, we show that continuous infusion of the CCR2 antagonist RS‐102895 into the lateral ventricles of renovascular hypertensive rats, attenuated the increase in blood pressure over a period of two months.These results suggest that upregulation of CCL2 and immune cell infiltration into the PVN precede the sustained increases in sympathetic activity and blood pressure observed in renovascular hypertension. These findings highlight CCL2‐CCR2 signalling and immune cells as new therapeutic targets for treating hypertension. Interestingly, these findings also suggest a specific interaction between the autonomic nervous system and the immune system in the regulation of sympathetic nerve activity and blood pressure.Support or Funding InformationThis work was supported by the National Health and Medical Research Council of Australia (GNT 1079680 to STY), the High Blood Pressure Research Council of Australia, the Rebecca L Cooper Medical Foundation, the Wade Institute and Ormond College ‐ University of Melbourne (to WSK) and the Victorian Government through the Operational Infrastructure Scheme. KE and AS are supported by the Australian Government Research Training Program Scholarships. STY is supported by an Australian Research Council Future Fellowship (FT170100363).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.