title: Abnormal CD161+immune cells and retinoic acid receptor-related orphan receptor γt-mediate enhanced IL-17F expression in the setting of genetic hypertension.
abstract: 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 TH17 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 γt (RORγt) 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 RORγt 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 RORγt 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 RORγt by digoxin decreased systolic blood pressure in SHRs.
  
  
  CONCLUSIONS
  SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.
authors.affiliation: Department of Internal Medicine and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: madhu-singh@uiowa.edu.
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Singh
authors.affiliation: Department of Internal Medicine and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Veterans Affairs Medical Center, Iowa City, Iowa.
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Cicha
authors.affiliation: Department of Internal Medicine and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, Iowa.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Department of Internal Medicine and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
authors.affiliation: Department of Internal Medicine and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Veterans Affairs Medical Center, Iowa City, Iowa; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Chapleau
authors.affiliation: Department of Internal Medicine and Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: francois-abboud@uiowa.edu.
authors.forename: François M
authors.initials: FM
authors.lastname: Abboud
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004077:Digoxin / Q000494:pharmacology; D006973:Hypertension / Q000276:immunology* / Q000503:physiopathology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D008297:Male; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013154:Spleen / Q000166:cytology; D051196:Toll-Like Receptor 3 / Q000819:agonists; D014664:Vasodilation
chemical_list: C515934:Il17a protein, rat; D020381:Interleukin-17; D055651:NK Cell Lectin-Like Receptor Subfamily B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C530472:TLR3 protein, rat; D051196:Toll-Like Receptor 3; D012313:RNA; D004077:Digoxin; D011070:Poly I-C
keywords: CD161; Hypertension; IL-17; T cells; T(H)17; Toll-like receptor; digoxin; gene expression; innate immune system; retinoic acid receptor–related orphan receptor γt; spontaneously hypertensive rat