DC isoketal-modified proteins activate T cells and promote hypertension
Annet Kirabo, … , Jackson Roberts II, David G. Harrison
Annet Kirabo, … , Jackson Roberts II, David G. Harrison
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4642-4656. https://doi.org/10.1172/JCI74084.
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Research Article

DC isoketal-modified proteins activate T cells and promote hypertension

Abstract

Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.

Authors

Annet Kirabo, Vanessa Fontana, Ana P.C. de Faria, Roxana Loperena, Cristi L. Galindo, Jing Wu, Alfiya T. Bikineyeva, Sergey Dikalov, Liang Xiao, Wei Chen, Mohamed A. Saleh, Daniel W. Trott, Hana A. Itani, Antony Vinh, Venkataraman Amarnath, Kalyani Amarnath, Tomasz J. Guzik, Kenneth E. Bernstein, Xiao Z. Shen, Yu Shyr, Sheau-chiann Chen, Raymond L. Mernaugh, Cheryl L. Laffer, Fernando Elijovich, Sean S. Davies, Heitor Moreno, Meena S. Madhur, Jackson Roberts II, David G. Harrison

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Figure 9

Transfer of hypertension by DCs.

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Transfer of hypertension by DCs. (A) DCs were obtained from either sham ...
(A) DCs were obtained from either sham or angiotensin II–infused mice, and 1 × 106 cells were adoptively transferred to recipient WT or Rag1–/– mice, and blood pressure was monitored using telemetry. (B) Systolic blood pressure in response to low-dose angiotensin II infusion (140 ng/kg/min) 10 days after DC adoptive transfer (n = 5–7, **P < 0.01). DCs were treated with 1 mM t-BHP, and isoketals were measured by flow cytometry using Alexa Fluor 488–tagged D11 antibody in (C) CD11b+/CD11c–, (D) CD11b+/CD11c+, and (E) CD11b–/CD11c+ cells. (F) Expression of CD86 in DCs. (G) Coculture of t-BHP–treated DCs with T cells promoted survival of CD8+ T cell. (H) Adoptive transfer of t-BHP–treated DCs in mice increased systolic blood pressure (n = 4–7, *P < 0.05, **P < 0.01, ***P < 0.001).