Ischemia-induced endogenous microglial Nrf2/HO-1 axis activation modulates neuroinflammation and restrains ischemic brain injury

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B540
Abstract ID: 4137

Presenting Author:
Ping-Chang Kuo , Assistant Research Professor at Indiana Univ. Sch. of Med.

Abstract:

Cerebral ischemia induces oxidative stress and inflammatory responses in the brain. Nrf2 is a transcription factor responsible for regulating cellular redox balance. The activation of exogenous Nrf2/HO-1 axis in microglia (MG) has been shown to offer protection against ischemic stroke. However, whether the induction of endogenous Nrf2/HO-1 axis specifically in MG plays a role in modulating MG phenotypes and restraining ischemic brain injury is unknown. We generated mice with MG-specific Nrf2 knockdown (MG-Nrf2KD) to elucidate the role of endogenous MG Nrf2 expression in ischemic stroke. We show that MG-Nrf2KD exacerbated ischemic brain injury. At the cellular level, MG-Nrf2KD altered MG phenotypes in ischemic stroke, in which increased inflammatory and decreased anti-inflammatory MG were detected. At the molecular level, attenuated Nrf2/HO-1 expression in MG contributed to the elevated inflammatory MG phenotype in MG-Nrf2KD stroke mice. Intriguingly, we observed diabetic stroke mice exhibited attenuated Nrf2/HO-1 axis activation in MG and exacerbated ischemic brain injury. Importantly, the induction of exogenous Nrf2/HO-1 axis in MG through pharmacological approaches ameliorated ischemic brain injury in diabetic mice. In sum, our findings provide cellular and molecular insights into ischemia-induced endogenous Nrf2/HO-1 axis activation in MG restraining brain injury that strengthens the therapeutic potential of targeting Nrf2/HO-1 axis in MG for ischemic stroke treatment.