AT2R Activation Prevents Microglia Pro-inflammatory Activation in a NOX-Dependent Manner: Inhibition of PKC Activation and p47^phox Phosphorylation by PP2A.

Microglia-induced reactive oxygen species production and inflammation play an imperative role in neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). It has been established that angiotensin II type-2 receptor (AT2R) activation is neuroprotective in central nervous system diseases like stroke and AD. However, the involvement of AT2R in NADPH oxidase (NOX)-mediated microglia activation is still elusive. Therefore, the present study investigated the role of AT2R in angiotensin II (Ang II) or Phorbol 12-myristate 13-acetate (PMA)-induced microglia activation in BV2 cells, primary microglia, p47^phox knockout (p47KO) microglia, and in vivo. Treatment of microglia with Ang II or PMA induced a significant generation and promoted pro-inflammatory microglia in a NOX-dependent manner. In contrast, AT2R activation by CGP42112A (CGP) inhibited NOX activation, duanyu1670 production, and pro-inflammatory microglia activation, while promoting the immunoregulatory microglia. This inhibitory effect of AT2R on NOX and pro-inflammatory activation was attenuated by AT2R antagonist, PD123319. Essentially, NOX inhibition (by DPI) or scavenging cellular duanyu1670 (by NAC) or p47KO microglia were immune to Ang II- or PMA-induced pro-inflammatory microglia activation. Mechanistically, AT2R, via activation of protein phosphatase-2A (PP2A), prevented the Ang II- or PMA-induced protein kinase C activation and phosphorylation of p47^phox, an effect that was reversed by the addition of PP2A inhibitor, Okadaic acid (OA). Importantly, inhibitor, Rottlerin, inhibited the Ang II- or PMA-induced p47^phox phosphorylation and duanyu1670 generation to the similar extent as AT2R activation. In addition, AT2R activation or p47KO prevented duanyu1670 production, pro-inflammatory microglial activation, and sickness behavior in mice model of neuroinflammation. Therefore, the present findings suggested that AT2R, via PP2A-mediated inhibition of prevents the NOX activation, duanyu1670 generation, and subsequent pro-inflammatory activation of microglia.

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