Neurohormonal modulation of the innate immune system is proinflammatory in the prehypertensive spontaneously hypertensive rat, a genetic model of essential hypertension.
BACKGROUND
Inflammation and autonomic dysfunction contribute to the pathophysiology of hypertension. Cholinergic stimulation suppresses innate immune responses. Angiotensin II (Ang II) induces hypertension and is associated with proinflammatory immune responses.


OBJECTIVE
Our goal was to define the innate immune response in a model of genetic hypertension and the influences of cholinergic stimulation and Ang II.


RESULTS
Studies were conducted on 4- to 5-week-old prehypertensive spontaneously hypertensive rats (SHRs) and age-matched normotensive control, Wistar Kyoto (WKY) rats. Isolated splenocytes were preexposed to nicotine or Ang II before Toll-like receptor (TLR) activation. Culture supernatants were tested for cytokines (tumor necrosis factor-α, interleukin [IL]-10, and IL-6). TLR-mediated cytokine responses were most pronounced with TLR7/8 and TLR9 activation and similar between WKY rats and SHRs. Nicotine and Ang II enhanced this TLR-mediated IL-6 response in prehypertensive SHR splenocytes. In contrast, nicotine suppressed the TLR-mediated IL-6 response in WKY rats, whereas Ang II had no effect. In vivo, nicotine enhanced plasma levels of TLR7/8-mediated IL-6 and IL-1β responses in prehypertensive SHRs but suppressed these responses in WKY rats. Flow cytometry revealed an increase in a CD161+ innate immune cell population, which was enhanced by nicotine in the prehypertensive SHR spleen but not in WKY.


CONCLUSIONS
There is a pronounced anti-inflammatory nicotinic/cholinergic modulation of the innate immune system in WKY rats, which is reversed in prehypertensive SHRs. 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.
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
Sailesh C
SC
Harwani
Mark W
MW
Chapleau
Kevin L
KL
Legge
Zuhair K
ZK
Ballas
François M
FM
Abboud
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000503:physiopathology*; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D018377:Neurotransmitter Agents / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology; D058246:Prehypertension / Q000503:physiopathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013154:Spleen / Q000187:drug effects / Q000473:pathology
D016207:Cytokines; D018377:Neurotransmitter Agents; D000804:Angiotensin II; D009538:Nicotine