Brain Transforming Growth Factor-β Resists Hypertension Via Regulating Microglial Activation

Abstract

Background and Purpose Hypertension is the major risk factor for stroke. Recent work unveiled that hypertension is associated with chronic neuroinflammation; microglia are the major players in neuroinflammation and the activated microglia elevate sympathetic nerve activity and blood pressure (BP). This study is to understand how brain homeostasis is kept from hypertensive disturbance and microglial activation at the onset of hypertension. Methods Hypertension was induced by subcutaneous delivery of angiotensin II and BP was monitored in conscious animals. Microglial activity was analyzed by flow cytometry and immunohistochemistry. Antibody, pharmacological chemical and recombinant cytokine were administered to the brain through intracerebroventricular (ICV) infusion. Microglial depletion was performed by ICV delivering diphtheria toxin to CD11b-DTR mice. Gene expression profile in sympathetic controlling nucleus was analyzed by customized qRT-PCR array. Results TGFβ is constitutively expressed in the brains of normotensive mice. Removal of TGFβ or blocking its signaling before hypertension induction accelerated hypertension progression, while supplementation of TGFβ1 substantially suppressed neuroinflammation, kidney norepinephrine level, and BP. By means of microglial depletion and adoptive transfer, we showed that the effects of TGFβ on hypertension are mediated through microglia. In contrast to the activated microglia in established hypertension, the resting microglia are immunosuppressive and important in maintaining neural homeostasis at the onset of hypertension. Further, we profiled the signature molecules of neuroinflammation and neuroplasticity associated with hypertension and TGFβ by qRT-PCR array. Conclusions Our results identify that TGFβ-modulated microglia are critical to keeping brain homeostasis responding to hypertensive disturbance.

Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

“…These studies showed changes in microglial morphology (enlarged soma, process retraction) and increased production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) [16][17][18]. Our results confirm that pressive Ang II leads to cerebral gliosis and extends this finding to another brain region, namely the hippocampus.…”

“…We decided to examine TNF-α in more detail rather than IL-6, based on previous evidence that hypothalamic microglia isolated from Ang II-treated mice exhibit a significant increase in TNF-α expression and a milder increase in IL-6 [17,18]. In line with the proposed hypothesis, ELISA analysis of hippocampal homogenates revealed a significant increase in TNF-α levels in mice infused with Ang II 1000 ng/kg/min compared to controls (p = 0.040, Fig.…”

“…Using anti-inflammatory approaches (with minocycline or IL-10 administered directly to the brain) or depleting microglia by intra-cerebro-ventricular administration of diphtheria toxin (DT) to transgenic CD11b-DT receptor mice, these studies have shown that inflammation and microglia play a central role in the development of high blood pressure in mice and rats [16,17]. While finding that inflammation influenced blood pressure, they also showed that hypertension, which was achieved via systemic infusion of angiotensin II (Ang II), was capable of producing increases in microglial density, soma enlargement, and reductions in microglial process length, as well as greater production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in this brain region [16][17][18].…”

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis

“…Early in TE12 infection, IFN-␥ was lower in IL-10 Ϫ/Ϫ mice than in WT mice, but later IFN-␥ production was higher and Th1 cells became more abundant. The reason for this change in pattern is not known, but microglial cells and NK cells can produce IFN-␥ independently of T cells in acute infection (47), and in the absence of IL-10, innate factors such as transforming growth factor ␤ (TGF-␤) may suppress IFN-␥ production prior to arrival of adaptive components of the immune response (48)(49)(50)(51)(52). Because TGF-␤ can induce the differentiation of Th17 cells (53-58), a potential dose-and cytokine-dependent role for TGF-␤ in the differential responses of TE12-and NSV-infected IL-10-deficient mice is under investigation.…”

The Association Between Plasma Furin and Cardiovascular Events After Acute Myocardial Infarction

“…Epithelial Na + channel (ENaC), which could be active by furin, associates with increased blood pressure [14]. However, transforming growth factor (TGF-β) is also activated by furin but it contributes to lower blood pressure [27]. BNP activated by furin associates with low blood pressure through its diuretic and vasodilatory actions.…”