Abnormal CD161+ immune cells and retinoic acid receptor-related orphan receptor ?t-mediate enhanced IL-17F expression in the setting of genetic hypertension.

ABSTRACT: BACKGROUND:Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated. OBJECTIVE:We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161+ immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor ?t (ROR?t) and a nicotinic proinflammatory innate immune response. METHODS:We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of ROR?t can attenuate hypertension in SHRs. RESULTS:SHRs exhibited an abnormally large population of CD161+ cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38 weeks. The SHR splenocytes constitutively expressed more ROR?t than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, in vivo inhibition of ROR?t by digoxin decreased systolic blood pressure in SHRs. CONCLUSIONS:SHRs have a markedly enhanced potential for ROR?t-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased ROR?t and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

SUBMITTER: Singh MV 

PROVIDER: S-EPMC5511774 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature