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RORγt‐Dependent Pro‐inflammatory Cytokine IL‐17F in SHR Impairs Endothelium‐Dependent Vascular Relaxation
Author(s) -
Singh Madhu V.,
Cicha Michael Z.,
Kumar Santosh,
Irani Kaikobad,
Chapleau Mark W.,
Abboud François M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1079.9
Subject(s) - medicine , endocrinology , cytokine , rar related orphan receptor gamma , population , t cell , phorbol , splenocyte , receptor , chemistry , immune system , immunology , biology , foxp3 , microbiology and biotechnology , spleen , signal transduction , protein kinase c , environmental health
We have previously shown that SHR (spontaneously hypertensive rat) have an abnormally large population of CD161+ immune cells that express RORγt (retinoic acid receptor related orphan receptor gamma) transcription factor. RORγt is the master regulator of T helper 17 (Th17) cell differentiation of CD4+ naive T cells that express CD161, IL‐17A and IL‐17F. This CD161+ abundance in the SHR spleen increases with age and produces a potent pro inflammatory cytokine IL‐17F in a RORγt‐dependent manner. In this study, we tested whether the enhanced inflammatory response seen in splenocytes is manifested in the vascular tissue of the SHR and contributes to a pathological response. We determined CD161+ cell infiltration of the aorta by flow cytometry and measured changes in RNA expression by real time quantitative PCR. We also performed wire myography on aortic rings to determine the effect of IL‐17F on vasorelaxation. We found significantly greater infiltration of CD161+ cells in age‐matched SHR aorta than in WKY (0.2% in WKY vs. 6.2% in SHR), whereas total CD4+ cell infiltration was not different (15.1% in WKY vs. 14.2% in SHR). Upon ex vivo treatment of aorta with phorbol 12‐myristate 13‐acetate (PMA) and ionomycin to induce cytokine production, both WKY and SHR showed increased IL‐17A RNA expression (1.6 fold in WKY vs. 2.4 fold in SHR), whereas IL‐17F expression was increased to a much greater extent in SHR aorta than in WKY (7.9 fold in WKY vs. 15.3 fold in SHR, P<0.05). These results are consistent with our previous findings of greater IL‐17F induction in SHR immune cells. Furthermore, we found that PMA‐ionomycin induces a modest increase in IL‐17A RNA expression in the peri‐vascular adipose tissue (PVAT) of both WKY and SHR (1.7 fold in WKY vs. 2.9 fold in SHR) with a much larger increase in IL‐17F RNA in SHR PVAT (2.8 fold in WKY vs. 13.9 fold in SHR, P<0.05). Treatment of aortic rings from WKY rats with IL‐17F, but not IL‐17A, impaired endothelium‐dependent relaxation of preconstricted vessels by acetylcholine in a dose‐dependent manner. The treatment did not affect endothelium‐independent, sodium nitroprusside‐induced vasorelaxation. We conclude that in SHR, a genetically predisposed abundance of CD161+ immune cells leads to a greater infiltration of these cells in the vasculature and increased potential for IL‐17F production. Moreover, IL‐17F impairs endothelium‐dependent vascular relaxation, a function previously unknown that would contribute to vascular pathology in SHR. Support or Funding Information NIH Program Project Grant to FMA (HL 14388) VA Merit Review Award to MWC (1I01BX001414), and AHA Innovative Research Grant to MVS (16IRG27260323).