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Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.

ABSTRACT: Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm?Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45(+)) and T lymphocytes (CD3(+) and CD4(+)) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3(+)/CD45RO(+)) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4(+) T cells and both CD4(+) and CD8(+) T cells that produce interferon-? in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II.

SUBMITTER: Itani HA

PROVIDER: S-EPMC4900908 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.

Itani Hana A HA McMaster William G WG Saleh Mohamed A MA Nazarewicz Rafal R RR Mikolajczyk Tomasz P TP Kaszuba Anna M AM Konior Anna A Prejbisz Aleksander A Januszewicz Andrzej A Norlander Allison E AE Chen Wei W Bonami Rachel H RH Marshall Andrew F AF Poffenberger Greg G Weyand Cornelia M CM Madhur Meena S MS Moore Daniel J DJ Harrison David G DG Guzik Tomasz J TJ

Hypertension (Dallas, Tex. : 1979) 20160523 1

Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and ...[more]

PMID: 27217403

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Project description:Mouse is the most widely used animal model in biomedical research, but it remains unknown what causes the large number of differentially regulated genes between human and mouse livers identified in recent years. In this report, we aim to determine whether these divergent gene regulations are primarily caused by environmental factors or some of them are the result of cell-autonomous differences in gene regulation in human and mouse liver cells. The latter scenario would suggest that many human genes are subject to human-specific regulation and can only be adequately studied in a human or humanized system. To understand the similarity and divergence of gene regulation between human and mouse livers, we performed stepwise comparative analyses in human, mouse, and humanized livers with increased stringency to gradually remove the impact of factors external to liver cells, and used bioinformatics approaches to retrieve gene networks to ascertain the regulated biological processes. We first compared liver gene regulation by fatty liver disease in human and mouse under the condition where the impact of genetic and gender biases was minimized, and identified over 50% of all commonly regulated genes, that exhibit opposite regulation by fatty liver disease in human and mouse. We subsequently performed more stringent comparisons when a single specific transcriptional or post-transcriptional event was modulated in vitro or vivo or in liver-specific humanized mice in which human and mouse hepatocytes colocalize and share a common circulation. Intriguingly and strikingly, the pattern of a high percentage of oppositely regulated genes persists under well-matched conditions, even in the liver of the humanized mouse model, which represents the most closely matched in vivo condition for human and mouse liver cells that is experimentally achievable. Gene network analyses further corroborated the results of oppositely regulated genes and revealed substantial differences in regulated biological processes in human and mouse cells. We also identified a list of regulated lncRNAs that exhibit very limited conservation and could contribute to these differential gene regulations. Our data support that cell-autonomous differences in gene regulation might contribute substantially to the divergent gene regulation between human and mouse livers and there are a significant number of biological processes that are subject to human-specific regulation and need to be carefully considered in the process of mouse to human translation.

Dataset Information

Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.

Publications

Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.

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