Volume 32, June 2023, Pages 50-56Author links open overlay panel, , , , , , , , , , , AbstractBackground

Preeclampsia (PE), new-onset hypertension (HTN), and organ dysfunction during the second half of pregnancy, is associated with an increase in inflammatory immune cells, including T helper 17 (Th17) cells. Studies have demonstrated that mitochondrial (mt) dysfunction is important in the pathogenesis of PE though causative factors have yet to be fully identified. Although Th17 cells, natural killer (NK) cells, and mt dysfunction contribute to HTN in the reduced uterine perfusion pressure (RUPP) rat model, the role of Th17 cells or IL-17 in mt dysfunction is unknown. Therefore, we hypothesize that RUPP stimulated Th17 cells cause HTN and mt dysfunction, which is alleviated with the blockade of IL-17.

Methods

On gestational day 12 (GD12), RUPP Th17 cells were transferred into normal pregnant (NP) Sprague Dawley rats. A subset of NP + RUPPTh17 rats received IL-17RC (100 pg/day) on GD14-19. Blood pressure (MAP), NK cells, and mt function were measured on GD19 in all groups.

Results

MAP increased in response to NP + RUPP Th17 compared to NP rats and was lowered with IL-17RC. Circulating and placental NK cells increased with NP + RUPP Th17 compared to NP and were lowered with IL-17RC. Renal mtROS increased in NP + RUPP Th17 compared to NP and was normalized with IL-17RC. Similar to PE women, placental mtROS decreased in NP + RUPP Th17 and was normalized with IL-17RC.

Conclusion

Our results indicate that IL-17RC inhibition normalizes HTN, NK cell activation, and multi-organ mt dysfunction caused by Th17 cells stimulated in response to placental ischemia.

Section snippetsBackground

Preeclampsia (PE) is a multi-system disorder of pregnancy characterized by new-onset hypertension and organ dysfunction occurring after the 20th week of gestation [1], [2], [3], [4]. Preeclampsia is associated with oxidative stress, endothelial dysfunction, and fetal growth restriction (FGR) [1], [2], [3], [5], [6], [7]. During a normal pregnancy, the placenta is a hypoxic environment until spiral arteries are remodeled to provide increased blood flow to the maturing placenta, and antioxidant

Animals

Timed-pregnant female Sprague Dawley (SD) rats (200–250 g) were purchased from Envigo (Indianapolis, IN, USA). Rats were housed in a temperature-controlled facility with a 12:12 h light/dark cycle and were fed and watered ad libitum. All procedures and handling complied with the guidelines of the University Of Mississippi Medical Center (UMMC) and are based on the principles in the National Institutes of Health Guide for the Care of Animals and were approved by the Institutional Animal Care and

Effect of Th17 adoptive transfer and IL-17 inhibition on blood pressure

Mean arterial pressure was increased in recipients of RUPP Th17 cells (NP + RUPP Th17;112 ± 1.07 mmHg, *p < 0.05 vs NP; n = 12) compared to the normal pregnant rats (NP) (92 ± 3 mmHg, n = 12). Hypertension was attenuated by the administration of soluble IL-17RC (NP + RUPPTh17 + IL-17RC) (98 ± 2.0 mmHg #p < 0.05 vs. NP + RUPPTh17; n = 12) (Fig. 1).

Effect of Th17 adoptive transfer and IL-17 inhibition on natural killer cell activation

Natural killer cell activation was increased in the NP + RUPPTh17 rat placental tissue (1.565 ± 0.51% Gated; *p < 0.05 vs NP; n = 10) in comparison to

Discussion

We sought to identify the role that IL-17 plays in causing mitochondrial dysfunction in response to Th17 cells in the pathophysiology of PE. Th17 cells have been shown to cause hypertension, activate NK cells, and cause a pro-inflammatory shift in multiple cytokines in the RUPP rat model of placental ischemia [1], [14], [15], [21], [22], [25], [27], [28], [29], [30], [31]. We demonstrate that the adoptive transfer of RUPP Th17 cells into NP recipient rats resulted in hypertension, NK cell

Conclusions

Collectively our data indicate the importance IL-17 has in the pathophysiology of the kidney and placenta when Th17 cells are activated, leading to activation of NK cells. Moreover, Th17 cell-mediated activation of NK cells leads to renal and placental mt dysfunction which is normalized by IL-17 inhibition. This may be the essential mechanism whereby blood pressure is normalized in IL-17 RC treated recipient rats. Future studies are needed to investigate the mitochondrial dysfunction seen

Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Funding

This study was supported by NIH grants RO1HD067541 (BL), P20GM121334 (BL, LMA), and R01HL151407 (DCC), and American heart association (AHA) early career award 19CDA34670055 (LMA).

Author contributions

B.B.L designed the study, S.F., E.D., J.H., T.T., L.M.A., N.H, K.E., O.H., N.C., and T.I. carried out the experiments and immunoassays. B.B.L. and S.F. collected, analyzed, and interpreted the data. B.B.L., S.F., E.D., and D.C.C. drafted the manuscript. All authors read and approved the final draft.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

ELISA data reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM104357 (UMMC Analytical Core) and the National Heart, Lung, and Blood Institute under Award Number P01HL51971 (UMMC Analytical Core).

References (55)C.M. Wilke et al.Deciphering the role of Th17 cells in human disease

Trends Immunol.

(2011)

M.S. Maddur et al.Th17 cells: biology, the pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies

Am. J. Pathol.

(2012)

M.W. Cunningham et al.Renal natural killer cell activation and mitochondrial oxidative stress; new mechanisms in AT1-AA mediated hypertensive pregnancy

Pregn. Hypertens

(2019)

F.H. Messerli et al.Essential hypertension

Lancet

(2007)

L.M. Amaral et al.Preeclampsia: long-term consequences for vascular health

Vasc. Health Risk Manage.

(2015)

S. Lisonkova et al.Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease

Am. J. Obstet. Gynecol.

(2013)

J. Mayrink R.T. Souza F.E. Feitosa E.A. Rocha Filho D.F. Leite J. Vettorazzi I.M. Calderon M.H. Sousa M.L. Costa P.N....E.M. George et al.Recent insights into the pathophysiology of preeclampsia

Exp. Rev. Obstet. Gynecol.

(2010)

O.K. Travis et al.Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia

Am. J. Physiol. Regul. Integr. Comp. Physiol.

(2020)

O.K. Travis et al.Chronic infusion of interleukin-17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

Physiol. Rep.

(2019)

V.R. Vaka et al.Role of mitochondrial dysfunction and reactive oxygen species in mediating hypertension in the reduced uterine perfusion pressure rat model of preeclampsia

Hypertension

(2018)

V.R. Vaka et al.Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia

Am. J. Physiol. Regul. Integr. Comp. Physiol.

(2020)

S. Illsinger et al.Preeclampsia and HELLP syndrome: impaired mitochondrial function in umbilical endothelial cells

Reprod. Sci.

(2010)

P. Evangeline Deer V. Ramana Vaka P., Kristen M. McMaster, M., Kedra Wallace, P., Denise C. Cornelius, P., Lorena M....D.C. Cornelius et al.Administration of interleukin-17 soluble receptor C suppresses TH17 cells, oxidative stress, and hypertension in response to placental ischemia during pregnancy

Hypertension

(2013)

S. Karbach et al.Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease

Arterioscler. Thromb. Vasc. Biol.

(2014)

K. Wallace et al.CD4+ T-helper cells stimulated in response to placental ischemia mediate hypertension during pregnancy

Hypertension

(2011)

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