Neurohormonal Modulation of the Innate Immune System is Pro-inflammatory in the Pre-hypertensive Spontaneously Hypertensive Rat, a Genetic Model of Essential Hypertension
Rationale: Inflammation and autonomic dysfunction contribute to the pathophysiology of hypertension. Cholinergic stimulation suppresses innate immune responses. Angiotensin II induces hypertension and is associated with pro-inflammatory immune responses.
Objective: Our goal was to define the innate immune response in a model of genetic hypertension and the influence of cholinergic stimulation and Ang II.
Methods and Results: Studies were conducted on 4-5 week old pre-hypertensive Spontaneously Hypertensive Rats (SHR) and age matched normotensive control, Wistar Kyoto (WKY) rats. Isolated splenocytes were pre-exposed to nicotine or Ang II prior to Toll-like Receptor (TLR) activation. Culture supernatants were tested for cytokines (TNFα, IL-10, and IL-6). TLR-mediated cytokine responses were most pronounced with TLR7/8 and TLR9 activation and similar between WKY and SHR. Nicotine and Ang II enhanced this TLR mediated IL-6 response in pre-hypertensive SHR splenocytes. In contrast, nicotine suppressed the TLR mediated IL-6 response in WKY, while Ang II had no effect. In vivo, nicotine enhanced plasma levels of TLR7/8 mediated IL-6 and IL-1β in pre-hypertensive SHR, but suppressed these responses in WKY. Flow cytometry revealed an increase in a CD161+ innate immune cell population, which was enhanced by nicotine in the pre-hypertensive SHR spleen, but not in WKY.
Conclusions: There is a pronounced anti-inflammatory nicotinic/cholinergic modulation of the innate immune system in WKY, which is reversed in pre-hypertensive SHR. The results support the novel concept that neurohormonal regulation of the innate immune system plays a role in the pathogenesis of genetic hypertension and provide putative molecular targets for treatment of hypertension.
- Received July 11, 2012.
- Accepted August 17, 2012.
- Copyright © 2012, American Heart Association