Abnormal CD1611 immune cells and retinoic acid receptor–related orphan receptor gt–mediate enhanced IL-17F expression in the setting of genetic hypertension

2019-03-07T16:06:14Z (GMT) by Madhu V. Singh
Background: Hypertension is considered an immunologic<br>disorder. However, the role of the IL-17 family in genetic<br>hypertension in the spontaneously hypertensive rat (SHR) has<br>not been investigated.<br>Objective: We tested the hypothesis that enhanced TH17<br>programming and IL-17 expression in abundant CD1611<br>immune cells in SHRs represent an abnormal proinflammatory<br>adaptive immune response. Furthermore, we propose that this<br>response is driven by the master regulator retinoic acid<br>receptor–related orphan receptor gt (RORgt) and a nicotinic<br>proinflammatory innate immune response.<br>Methods: We measured expression of the CD161 surface<br>marker on splenocytes in SHRs and normotensive control<br>Wistar-Kyoto (WKY) rats from birth to adulthood. We<br>compared expression of IL-17A and IL-17F in splenic cells<br>under different conditions. We then determined the functional<br>effect of these cytokines on vascular reactivity. Finally, we tested<br>whether pharmacologic inhibition of RORgt can attenuate<br>hypertension in SHRs.<br>Results: SHRs exhibited an abnormally large population of<br>CD1611 cells at birth that increased with age, reaching more<br>than 30% of the splenocyte population at 38 weeks. The SHR<br>splenocytes constitutively expressed more RORgt than those of<br>WKY rats and produced more IL-17F on induction. Exposure<br>of WKY rat aortas to IL-17F impaired endothelium-dependent<br>vascular relaxation, whereas IL-17A did not. Moreover, in vivo inhibition of RORgt by digoxin decreased systolic blood<br>pressure in SHRs.<br>Conclusions: SHRs have a markedly enhanced potential for<br>RORgt-driven expression of proinflammatory and<br>prohypertensive IL-17F in response to innate immune<br>activation. Increased RORgt and IL-17F levels contribute to<br>SHR hypertension and might be therapeutic targets.<br>