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

作者：Singh Madhu V^*; Cicha Michael Z; Kumar Santosh; Meyerholz David K; Irani Kaikobad; Chapleau Mark W; Abboud Francois M^*

来源：Journal of Allergy and Clinical Immunology, 2017, 140(3): 809-+.

DOI：10.1016/j.jaci.2016.11.039

• Hypertension
• innate immune system
• Toll-like receptor
• retinoic acid receptor-related orphan receptor gamma t
• digoxin
• T cells
• T(H)17
• CD161
• IL-17
• spontaneously hypertensive rat
• gene expression

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 T(H)17 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 gamma t (ROR gamma 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 gamma 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 gamma 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 gamma t by digoxin decreased systolic blood pressure in SHRs.
Conclusions: SHRs have a markedly enhanced potential for ROR gamma t-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased ROR gamma t and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

• 出版日期2017-9