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.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…Even more striking, the administration of the ACE inhibitor lisinopril after the establishment of EAE actually reversed the severity of animal paralysis. Both in their original study and in a followup investigation, this group identified angiotensin II-induced expression of transforming growth factorb as being important in the pathogenesis of EAE (Lanz et al, 2010). Several other studies have demonstrated a role of ACE and angiotensin II in models of autoimmunity, including rheumatoid arthritis and experimental autoimmune uveoretinitis (Dalbeth et al, 2005;Sagawa et al, 2005;Okunuki et al, 2009).…”

Cross talk between AT1receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

“…EGFR signaling is required for TLR4-mediated activation of NF-B in response to lipopolysaccharide (20), and its activation by ANG II can occur within a similar time course (in minutes) as the effect we describe here for ANG II-TLR4-ROS production. Another possibility is that ANG II induces the upregulation and activation of the cytokine transforming growth factor-␤ by trombospondin-1 (36), which, in turn, activates TLR4 pathways in macrophages to induce TNF-␣ production (42). Clearly, future studies are warranted to more precisely characterize the signaling mechanisms underlying the ANG II-AT 1a R-TLR4 cross talk in mediating microglial ROS production in the PVN.…”

Protein kinase Cβ as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis

“…Indeed, these analyses revealed a more complex inhibition of leukocyte transendothelial migration pathways involving the suppression of additional key targets such as the Rho GTPase family member Rac1, which is induced by PKCβ (26) and has been shown to be critically involved in immunomodulatory efficacy of IFN-β in EAE (27), or the Rap guanine nucleotide exchange factor (GEF) 3 (Rapgef3), which is critically involved in the inflammatory vascular permeability (28). In addition, there was down-regulation of the transforming growth factor (TGF)-β pathway, which is induced during endothelial inflammation via PKCβ (29), and which is-when active in the CNS during autoimmune neuroinflammation-critical for the recruitment of encephalitogenic T cells (30,31) (Fig. S4).…”