CD1d-Dependent Natural Killer T Cells Mediate Hypertension and Vascular Injury Through Interleukin-17A

Overview

Journal J Am Heart Assoc

Specialty Cardiology & Vascular Diseases

Date 2023 Jun 29

PMID 37382154

Authors

Xue Xiao

Cui-Liu Hou

Yun-Long Zhang

Hui Yang

Xiao-Xiao Wang

Hong-Xia Wang

Affiliations

Soon will be listed here.

Abstract

Background Different T-lymphocyte subsets, including CD1d-dependent natural killer T (NKT) cells, play distinct roles in hypertension, highlighting the importance of identifying key immune cells for its treatment. This study aimed to determine the unknown effects of CD1d-dependent NKT cells on hypertension and vascular injury. Methods and Results Hypertension models were induced in male CD1d knockout (CD1dko), wild-type, and adoptive bone marrow transfer mice by angiotensin II (Ang II) or deoxycorticosterone acetate salt. Blood pressure was measured by the tail-cuff system and radiotelemetry. Vascular injury was assessed by histologic studies or aortic ring assay. Inflammation was detected by flow cytometry, quantitative real-time polymerase chain reaction, or ELISA. Results showed that Ang II infusion significantly reduced CD1d expression and NKT cell numbers in the aorta of mice. CD1dko mice exhibited worsened blood pressure elevation, vascular injury, and inflammatory response induced by Ang II or deoxycorticosterone acetate salt. However, these effects were markedly reversed in wild-type mice treated with NKT cell-specific activator. Adoptive transfer of CD1dko bone marrow cells to wild-type mice also significantly worsened Ang II-induced responses. Mechanistically, CD1dko increased Ang II-induced interleukin-6 production and activated signal transducer and activator of transcription 3 and orphan nuclear receptor γ, subsequently inducing interleukin-17A production. Neutralizing interleukin-17A partially reversed Ang II-induced hypertension and vascular injury in CD1dko mice. In addition, levels of NKT cells were lower in the blood of patients with hypertension (n=57) compared with normotensive individuals (n=87). Conclusions These findings reveal a previously unknown role for CD1d-dependent NKT cells in hypertension and vascular injury, indicating that NKT cell activation could be a promising therapeutic target for hypertension.

References

Grajewski R, Hansen A, Agarwal R, Kronenberg M, Sidobre S, Su S . Activation of invariant NKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-gamma production and dampening of the adaptive Th1 and Th17 responses. J Immunol. 2008; 181(7):4791-7. PMC: 2597425. DOI: 10.4049/jimmunol.181.7.4791. View

Zhou L, Ivanov I, Spolski R, Min R, Shenderov K, Egawa T . IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007; 8(9):967-74. DOI: 10.1038/ni1488. View

Rai A, Narisawa M, Li P, Piao L, Li Y, Yang G . Adaptive immune disorders in hypertension and heart failure: focusing on T-cell subset activation and clinical implications. J Hypertens. 2020; 38(10):1878-1889. DOI: 10.1097/HJH.0000000000002456. View

Bomfim G, Rodrigues F, Carneiro F . Are the innate and adaptive immune systems setting hypertension on fire?. Pharmacol Res. 2017; 117:377-393. DOI: 10.1016/j.phrs.2017.01.010. View

Wang H, Li W, Hou C, Lai S, Zhang Y, Tian C . CD1d-dependent natural killer T cells attenuate angiotensin II-induced cardiac remodelling via IL-10 signalling in mice. Cardiovasc Res. 2018; 115(1):83-93. DOI: 10.1093/cvr/cvy164. View

Saleh M, Norlander A, Madhur M . Inhibition of Interleukin 17-A but not Interleukin-17F Signaling Lowers Blood Pressure and Reduces End-organ Inflammation in Angiotensin II-induced Hypertension. JACC Basic Transl Sci. 2017; 1(7):606-616. PMC: 5337944. DOI: 10.1016/j.jacbts.2016.07.009. View

Cui C, Fan J, Zeng Q, Cai J, Chen Y, Chen Z . CD4 T-Cell Endogenous Cystathionine γ Lyase-Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation. Circulation. 2020; 142(18):1752-1769. DOI: 10.1161/CIRCULATIONAHA.119.045344. View

Oh K, Byoun O, Ham D, Kim Y, Lee D . Invariant NKT cells regulate experimental autoimmune uveitis through inhibition of Th17 differentiation. Eur J Immunol. 2011; 41(2):392-402. DOI: 10.1002/eji.201040569. View

Darlington P, Stopnicki B, Touil T, Doucet J, Fawaz L, Roberts M . Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis. Front Immunol. 2018; 9:834. PMC: 5951114. DOI: 10.3389/fimmu.2018.00834. View

10.

Cao H, Fang J, Zhang Y, Zou L, Han X, Yang J . Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice. J Mol Cell Cardiol. 2019; 137:34-45. DOI: 10.1016/j.yjmcc.2019.09.010. View

11.

Chen S, Agrawal D . Dysregulation of T cell subsets in the pathogenesis of hypertension. Curr Hypertens Rep. 2015; 17(2):8. PMC: 5643157. DOI: 10.1007/s11906-014-0521-1. View

12.

Madhur M, Lob H, McCann L, Iwakura Y, Blinder Y, Guzik T . Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension. 2009; 55(2):500-7. PMC: 2819301. DOI: 10.1161/HYPERTENSIONAHA.109.145094. View

13.

Mars L, Araujo L, Kerschen P, Diem S, Bourgeois E, Pham Van L . Invariant NKT cells inhibit development of the Th17 lineage. Proc Natl Acad Sci U S A. 2009; 106(15):6238-43. PMC: 2669382. DOI: 10.1073/pnas.0809317106. View

14.

Getz G, Reardon C . Natural killer T cells in atherosclerosis. Nat Rev Cardiol. 2017; 14(5):304-314. DOI: 10.1038/nrcardio.2017.2. View

15.

Homma T, Kinugawa S, Takahashi M, Sobirin M, Saito A, Fukushima A . Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice. J Mol Cell Cardiol. 2013; 62:179-88. DOI: 10.1016/j.yjmcc.2013.06.004. View

16.

Wang Y, Sedimbi S, Lofbom L, Singh A, Porcelli S, Cardell S . Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells. Mucosal Immunol. 2017; 11(1):131-143. PMC: 5638666. DOI: 10.1038/mi.2017.34. View

17.

Bedard M, Shrestha D, Priestman D, Wang Y, Schneider F, Matute J . Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells. Proc Natl Acad Sci U S A. 2019; 116(47):23671-23681. PMC: 6876220. DOI: 10.1073/pnas.1910097116. View

18.

Singh T, Carvalho A, Amorim Sacramento L, Grice E, Scott P . Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis. PLoS Pathog. 2021; 17(10):e1009693. PMC: 8570469. DOI: 10.1371/journal.ppat.1009693. View

19.

Zhang R, McNerney K, Riek A, Bernal-Mizrachi C . Immunity and Hypertension. Acta Physiol (Oxf). 2020; 231(1):e13487. PMC: 7606441. DOI: 10.1111/apha.13487. View

20.

Orejudo M, Garcia-Redondo A, Rodrigues-Diez R, Rodrigues-Diez R, Santos-Sanchez L, Tejera-Munoz A . Interleukin-17A induces vascular remodeling of small arteries and blood pressure elevation. Clin Sci (Lond). 2020; 134(5):513-527. DOI: 10.1042/CS20190682. View