Microglial TNF‐α mediates enhancement of dopaminergic degeneration by brain angiotensin

In vitro and in vivo models of Parkinson's disease were used to investigate whether TNF‐α plays a major role in the enhancement of the microglial response and dopaminergic degeneration induced by brain angiotensin hyperactivity. Treatment of primary mesencephalic cultures with low doses of the neurotoxin MPP⁺ induced a significant loss of dopaminergic neurons, which was enhanced by cotreatment with angiotensin II and inhibited by TNF‐α inhibitors. Treatment of primary cultures with angiotensin induced a marked increase in levels of TNF‐α, which was inhibited by treatment with angiotensin type‐1‐receptor antagonists, NADPH‐oxidase inhibitors and NFK‐β inhibitors. However, TNF‐α levels were not significantly affected by treatment with angiotensin in the absence of microglia. The microglial origin of the angiotensin‐induced increase in TNF‐α levels was confirmed using dopaminergic (MES 23.5) and microglial (N9) cell lines. Inhibition of the microglial Rho‐kinase activity also blocked the AII‐induced increase in TNF‐α levels. Treatment of the dopaminergic cell line with TNF‐α revealed that NFK‐β activation mediates the deleterious effect of microglial TNF‐α on dopaminergic neurons. Treatment of mice with MPTP also induced significant increases in striatal and nigral TNF‐α levels, which were inhibited by angiotensin type‐1‐receptor antagonists or NFK‐β inhibitors. The present results show that microglial TNF‐α plays a major role in angiotensin‐induced dopaminergic cell death and that the microglial release of TNF‐α is mediated by activation of angiotensin type‐1 receptors, NADPH‐oxidase, Rho‐kinase and NFK‐β. GLIA 2014;62:145–157