Angiotensin II sustains brain inflammation in mice via TGF-β
Tobias V. Lanz, … , Tony Wyss-Coray, Lawrence Steinman
Tobias V. Lanz, … , Tony Wyss-Coray, Lawrence Steinman
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2782-2794. https://doi.org/10.1172/JCI41709.
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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 4

Downregulation of pSMAD after CA treatment.

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Downregulation of pSMAD after CA treatment. (A) In vivo bioluminescence ...
(A) In vivo bioluminescence of diseased SBE-Luc mice depicts pSMAD signaling. Mice were imaged on the indicated days after immunization. The highly increased level of pSMAD signaling in the vehicle control group (top row) is almost completely abrogated by CA treatment (bottom row). One representative mouse of each group is followed up. sr, steradian. (B and C) Statistical evaluation of the experiment shown in A. Mean intensity of bioluminescence in (B) brains and (C) spinal cords of immunized SBE-Luc mice. Mean ± SEM of each group is shown (n = 5 per group). *P < 0.05 (Student’s t test). (D) Cerebellar slices are stained for pSMAD, confirming its upregulation during EAE and its downregulation due to CA treatment. One representative slide of each group is shown. Scale bars: 100 μm. (E) Statistical evaluation of the experiment shown in D. pSMAD staining intensities were evaluated with MetaMorph software and normalized on the healthy control group. Statistical analysis of 6 cerebellar slices per mouse is shown (n = 5 mice per group; mean ± SEM). *P < 0.02 (Student’s t test). (F–I) Fluorescence double staining of inflamed spinal cords for pSMAD (red) and the following cell markers (blue): (F) astrocytes, (G) microglial cells, (H) neurons, and (I) CD4+ T cells. T cells show high levels of nuclear staining for pSMAD, and therefore are responsive to TGF-β, as do microglia and neurons but not astrocytes. Spinal cords are from untreated diseased mice. Scale bars: 50 μm.