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Background: Activated microglia is essential for hematoma clearance and recovery after intracerebral hemorrhage (ICH). This study aims to evaluate the effect of microglial functional transformation in hematoma clearance after ICH. Through in vitro and in vivo experiments, we also investigate whether Nuclear factor erythroid 2-related factor 2 (Nrf2) -mediated microglial phagocytosis and inflammatory response plays a role in hematoma clearance and functional recovery after ICH.Methods: For in vitro experiments, BV-2 cells were cultured and randomly divided into 4 groups, including normal control, microglia + Nrf2-siRNA (100 nmol/L), microglia + monascin (15 µM), and microglia + Xuezhikang (200 µg/mL) groups. For vivo experiments, 42 mice were divided into2 groups, i.e., sham, ICH+vehicle, ICH+Nrf2-/-, ICH+monascin (10mg/kg/day, twice) and ICH+Xuezhikang (0.2g/kg/day, twice) groups. Further, neurologic scores, hemoglobin levels, microglial phagocytosis, brain expression of CD80/Trem1/TNF-α (pro-inflammatory cytokines),and CD206/Trem2/BDNF(anti-inflammatory cytokines) were analyzed 72 hours after surgery. Results: The results showed that Nrf2 agonists improved neurological deficits and decreased hemoglobin levels after ICH through regulating microglial functional transformation. Administration of Nrf2 agonist- monascin/ Xuezhikang improved microglia-mediated phagocytosis of erythrocytes and bio-particles through Nrf2 upregulation. Alternatively, monascin/ Xuezhikang promoted the expression of Triggering receptor II expressed on myeloid cells(Trem2), CD206, and BDNF while inhibiting the expression of Trem1,CD80, and TNF-α in microglia. Conversely, Nrf2 inhibition (Nrf2 siRNA or Nrf2-/-) demonstrated conflicting results after ICH.Conclusion: Microglial functional transformations are implicated in hematoma clearance after ICH. Nrf2 activation leads to microglial functional transformation and phagocytic responses then exert its neuroprotection after ICH. Nrf2 activator (Monascin /Xuezhikang) improves hematoma clearance and alleviates neuroinflammation by regulating microglial functional alteration after ICH.

Activated microglia is essential for hematoma clearance and recovery after intracerebral hemorrhage (ICH). This study aims to evaluate the effect of microglial functional transformation in hematoma clearance after ICH. Through in vitro and in vivo experiments, we also investigate whether Nuclear factor erythroid 2-related factor 2 (Nrf2) -mediated microglial phagocytosis and inflammatory response plays a role in hematoma clearance and functional recovery after ICH. In vitro experiments, BV-2 cells were cultured and randomly divided into 4 groups, including normal control, microglia + Nrf2-siRNA (100 nmol/L), microglia + monascin (15 µM), and microglia + Xuezhikang (200 µg/mL) groups. In vivo experiments, 42 mice were divided into 2 groups, i.e., sham, ICH+vehicle, ICH+Nrf2-/-, ICH+monascin (10mg/kg/day, twice) and ICH+ Xuezhikang (0.2g/kg/day, twice) groups. Further, neurologic scores, hemoglobin levels, microglial phagocytosis, brain expression of CD80/Trem1/TNF-α (pro-inflammatory cytokines), and CD206/Trem2/ BDNF(anti-inflammatory cytokines) were analyzed 72 hours after surgery. The results showed that Nrf2 agonists improved neurological deficits and decreased hemoglobin levels after ICH through regulating microglial functional transformation. Administration of Nrf2 agonist- monascin/ Xuezhikang improved microglia-mediated phagocytosis of erythrocytes and bio-particles through Nrf2 upregulation. Alternatively, monascin/ Xuezhikang promoted the expression of Triggering receptor II expressed on myeloid cells(Trem2), CD206, and BDNF while inhibiting the expression of Trem1,CD80, and TNF-α in microglia. Conversely, Nrf2 inhibition (Nrf2 siRNA or Nrf2-/-) demonstrated conflicting results after ICH. Microglial functional transformations are implicated in hematoma clearance after ICH. Nrf2 activation leads to microglial functional transformation and phagocytic responses then exert its neuroprotection after ICH. Nrf2 activator (Monascin /Xuezhikang) improves hematoma clearance and alleviates neuroinflammation by regulating microglial functional alteration after ICH.

Background To explore the effect of microglial functional transformation in hematoma clearance following intracerebral hemorrhage (ICH), and investigate whether Nuclear factor erythroid 2-related factor 2 (Nrf2) -mediated microglial phagocytosis and inflammatory response is beneficial for hematoma clearance and functional recovery in vitro and in vivo experiments after ICH. Methods In vitro experiments, BV-2 cells were cultured and randomly divided into 4 groups: normal control, microglia + Nrf2-siRNA (100 nmol/L), microglia + monascin (15 µM), microglia + Xuezhikang (200 µg/mL). In vivo experiments, 42 mice were divided into sham, ICH+vehicle, ICH+Nrf2-/-, ICH+monascin (10mg/kg/day, twice) and ICH+Xuezhikang (0.2g/kg/day, twice). Neurologic scores, hemoglobin levels, microglial phagocytosis, brain expression of CD80 /Trem1/TNF-α (pro-inflammatory cytokines) as well as CD206/Trem2/BDNF (anti-inflammatory cytokines) were analyzed at 72 hours after surgery. Results The results showed that Nrf2 agonists improved neurological deficits and decreased hemoglobin levels after ICH. The administration of Nrf2 agonist- monascin/ Xuezhikang enhanced microglia-mediated phagocytosis of erythrocytes and bioparticles by up-regulating Nrf2. Alternatively, monascin/Xuezhikang promoted the expressions of Triggering receptor II expressed on myeloid cells (Trem2), CD206 and BDNF, while inhibited the expressions of Trem1,CD80 and TNF-αexpressed in microglia. Conversely, Nrf2 inhibition (Nrf2 siRNA or Nrf2-/-) showed the opposite results following ICH. Conclusions Microglial functional transformation are involved in hematoma clearance following ICH. Nrf2 activation contributes to microglial functional transformation and phagocytic responses then exerts its neuroprotection after ICH. Nrf2 activator (Monascin/Xuezhikang) enhances hematoma clearance and alleviates neuroinflammation via the regulation of microglial functional alteration following ICH.