JACI-CD161-SinghMV-2017.pdf (3.79 MB)
Abnormal CD1611 immune cells and retinoic acid receptor–related orphan receptor gt–mediate enhanced IL-17F expression in the setting of genetic hypertension
journal contribution
posted on 2019-03-07, 16:06 authored by Madhu V. SinghBackground: 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 CD1611
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 gt (RORgt) 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 RORgt can attenuate
hypertension in SHRs.
Results: SHRs exhibited an abnormally large population of
CD1611 cells at birth that increased with age, reaching more
than 30% of the splenocyte population at 38 weeks. The SHR
splenocytes constitutively expressed more RORgt 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 RORgt by digoxin decreased systolic blood
pressure in SHRs.
Conclusions: SHRs have a markedly enhanced potential for
RORgt-driven expression of proinflammatory and
prohypertensive IL-17F in response to innate immune
activation. Increased RORgt and IL-17F levels contribute to
SHR hypertension and might be therapeutic targets.
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 CD1611
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 gt (RORgt) 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 RORgt can attenuate
hypertension in SHRs.
Results: SHRs exhibited an abnormally large population of
CD1611 cells at birth that increased with age, reaching more
than 30% of the splenocyte population at 38 weeks. The SHR
splenocytes constitutively expressed more RORgt 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 RORgt by digoxin decreased systolic blood
pressure in SHRs.
Conclusions: SHRs have a markedly enhanced potential for
RORgt-driven expression of proinflammatory and
prohypertensive IL-17F in response to innate immune
activation. Increased RORgt and IL-17F levels contribute to
SHR hypertension and might be therapeutic targets.
