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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Singh, Madhu V.^1,2  Cicha, Michael Z.^1,2,4  Kumar, Santosh^1,2  Meyerholz, David K.⁵  Irani, Kaikobad^1,2  Chapleau, Mark W.^1,2,3,4  Abboud, Francois M.^1,2,3 

[1] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA

[2] Univ Iowa, Abboud Cardiovasc Res Ctr, Carver Coll Med, Iowa City, IA 52242 USA

[3] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA USA

[4] Vet Affairs Med Ctr, Iowa City, IA 52242 USA

[5] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA

关键词: 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;   

DOI  :  10.1016/j.jaci.2016.11.039

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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