Abstract 168: Abnormal Pro-inflammatory Regulation of the Innate Immune System in Genetic Hypertension
Immune cells from patients with essential hypertension are hyper-responsive to activation of toll-like receptor (TLR) 4 with lipopolysaccharide. Activation of the alpha7 nicotinic cholinergic receptor exerts an anti-inflammatory effect on innate immune cells. We hypothesized that this anti-inflammatory cholinergic response is lacking in the Spontaneously Hypertensive Rat (SHR) and recently reported that nicotine suppresses TLR7 and TLR9 mediated IL-6 secretion by isolated splenocytes of WKY rats; whereas, it dramatically enhances IL-6 secretion in SHR. Here we aimed to confirm these effects in vivo and identify potential cellular mediators of the observed immune responses. Flow cytometry on splenocytes revealed a greater number of CD3-/CD8dim innate immune cells in SHR (4.0±0.56%), compared to WKY (2.97±0.6%)(n=3, p<0.05). Using CD161, a cell surface marker of natural kille/dendritic cells and activated macrophages, we show that the CD3-/CD8dim+/CD161+ and CD3-/ CD8-/CD161+ innate immune cells are increased in SHR (5±0.5% and 4.6±0.85, respectively), compared to WKY (0.8±0.3% and 1.0±0.5%, respectively) (n=3, p<0.05). Moreover, nicotine expanded both cell populations in the SHR to 6.4% and 6.0%, respectively, but had no effect in WKY, where the populations remained at 1.1% and 1.2%, respectively. In vivo, we infused saline or nicotine (15mg/kg/day) over 24 hours using subcutaneous pumps. At 20 hrs, animals received an intraperitoneal injection of a TLR7 ligand (Clo97). Serum was collected at the end of the 24 hr infusion. Similar to previous in vitro results, nicotine suppressed the serum IL-6 response to i.p. Clo97 from 108±28 pg/ml in WKY (n=4) to 12±7 pg/ml (p<0.05) in 4-5 week old WKY, but dramatically enhanced the IL-6 response in SHR (n=4), following i.p. Clo97, from 58±20 pg/ml to 187±38 pg/ml (p<0.05). We conclude that there is a dominant innate immune cell population in SHR prior to the development of hypertension that expands with cholinergic stimulation and may contribute to the pronounced pro-inflammatory increase in IL-6 following cholinergic stimulation. We speculate that this abnormality in the pre-hypertensive state contributes to the development of genetic hypertension and may play a role in human essential hypertension.
- © 2012 by American Heart Association, Inc.