Angiotensin II sustains brain inflammation in mice via TGF-β
Tobias V. Lanz, Zhaoqing Ding, Peggy P. Ho, Jian Luo, Ankur N. Agrawal, Hrishikesh Srinagesh, Robert Axtell, Hui Zhang, Michael Platten, Tony Wyss-Coray, Lawrence Steinman
Tobias V. Lanz, Zhaoqing Ding, Peggy P. Ho, Jian Luo, Ankur N. Agrawal, Hrishikesh Srinagesh, Robert Axtell, Hui Zhang, Michael Platten, Tony Wyss-Coray, Lawrence Steinman
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Research Article Immunology

Angiotensin II sustains brain inflammation in mice via TGF-β

Abstract

The renin-angiotensin-aldosterone system (RAAS) is a key hormonal system regulating blood pressure. However, expression of RAAS components has recently been detected in immune cells, and the RAAS has been implicated in several mouse models of autoimmune disease. Here, we have identified Ang II as a paracrine mediator, sustaining inflammation in the CNS in the EAE mouse model of MS via TGF-β. Ang II type 1 receptors (AT1Rs) were found to be primarily expressed in CNS-resident cells during EAE. In vitro, astrocytes and microglia responded to Ang II treatment by inducing TGF-β expression via a pathway involving the TGF-β–activating protease thrombospondin-1 (TSP-1). TGF-β upregulation in astrocytes and microglia during EAE was blocked with candesartan (CA), an inhibitor of AT1R. Treatment of EAE with CA ameliorated paralysis and blunted lymphocyte infiltration into the CNS, outcomes that were also seen with genetic ablation of AT1Ra and treatment with an inhibitor of TSP-1. These data suggest that AT1R antagonists, frequently prescribed as antihypertensives, may be useful to interrupt this proinflammatory, CNS-specific pathway in individuals with MS.

Authors

Tobias V. Lanz, Zhaoqing Ding, Peggy P. Ho, Jian Luo, Ankur N. Agrawal, Hrishikesh Srinagesh, Robert Axtell, Hui Zhang, Michael Platten, Tony Wyss-Coray, Lawrence Steinman

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Figure 2

Ang II stimulates TGF-β production and activation in primary cultured astrocytes and microglia.

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Ang II stimulates TGF-β production and activation in primary cultured as...
(A and B) Total TGF-β in supernatants of primary cultured cells. (A) In microglial cells, total production of TGF-β can be almost doubled by stimulation with Ang II. This effect can be abrogated by inhibition of AT1R with losartan. (B) In contrast, astrocytes produce much less and do not upregulate total TGF-β production upon Ang II stimulation. (C and D) Active TGF-β in supernatants of primary cultured cells. (C) Ang II does not have any effect on activation of TGF-β in microglia, as opposed to (D) astrocytes, which triple the amount of active TGF-β in their supernatants upon Ang II stimulation. This effect is also AT1R dependent and can be disrupted by losartan and by knockout of AT1R. Representative data are shown from 1 of 2 independent experiments; measurements were carried out in triplicates (mean ± SEM). *P < 0.05, **P < 0.01 (Student’s t test).