Abnormal CD161+ Immune Cells and RORΓT Mediated Enhanced IL-17F Expression in Genetic Hypertension

Publication date: Available online 16 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Madhu V. Singh, Michael Z. Cicha, Santosh Kumar, David K. Meyerholz, Kaikobad Irani, Mark W. Chapleau, François M. Abboud
BackgroundHypertension is considered an immunological disorder. However, the role of IL-17 family in genetic hypertension of the spontaneously hypertensive rat (SHR) has not been investigated.ObjectiveWe tested the hypothesis that enhanced Th17 programming and IL-17 expression in abundant CD161+ immune cells in SHR represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator RORγt and a nicotinic proinflammatory innate immune response.MethodsWe measured the expression of CD161 surface marker on splenocytes in SHR 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 pharmacological inhibition of RORγt can attenuate hypertension in SHR.ResultsThe SHR 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 RORγt than WKY and produced more IL-17F upon induction. Exposure of WKY aorta to IL-17F impaired endothelium-dependent vascular relaxation whereas IL-17A did not. Moreover, in vivo inhibition of RORγt by digoxin lowered systolic blood pressure in SHR.ConclusionsSHR has a markedly enhanced potential for RORγt –driven expression of proinflammatory, pro-hypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F contribute to SHR hypertension and may be potential therapeutic targets.

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Teaser

Hypertension is considered to be an autoimmune dysfunction. We show in a genetic hypertension model that inhibition of RORγt, the master regulator transcription factor that promotes Th17 differentiation and IL-17F production, reduces hypertension.


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