Abstract
The macrophage scavenger receptor 1 (MSR1)-induced resolution of neuroinflammation may be a novel therapeutic strategy for ischemic stroke. Our previous study showed that the neuroprotective and anti-inflammatory effects of phthalide are associated with the inhibition of the post-ischemic damage-associated molecular pattern (DAMP)/Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of the phthalide derivative CD21 on ischemic brain injury and the mechanism underlying MSR1-induced resolution of neuroinflammation. Using a rat model of 2 h transient middle cerebral artery occlusion (MCAO), MSR1-induced peroxiredoxin1 (PRX1) clearance in RAW264.7 macrophages were investigated. We show here that CD21 significantly ameliorated infarct volumes and neurological deficits in a dose-dependent manner with a ≥ 12 h therapeutic time window. Moreover, administration of 5 mg/kg/day CD21 over 24 h significantly reduced pathological damages, with associated inhibition of PRX1 expression, reduced TLR4/nuclear factor-κB activation and the suppression of the inflammatory response in MCAO rats. Furthermore, the expression of MAFB/MSR1 in the ischemic brain was elevated and the phagocytosis of PRX1 in CD68-positive macrophages isolated from the ischemic brain was enhanced. Further in vitro studies show that CD21 (20 μM) strongly enhanced the Msr1 mRNA and MSR1 protein levers in RAW264.7 cells and PRX1 internalization in cellular lysosomes, which were significantly reversed by N-acetylcysteine treatment. These results suggest that CD21 may exert neuroprotective and anti-inflammatory effects with a wide time window for the treatment of ischemic stroke. The anti-stroke effects of CD21 appear to be mediated partially via the induction of MSR1-promoted DAMP (PRX1) clearance, TLR4/nuclear factor-κB pathway inhibition, and the resolution of inflammation.
The neuroprotective action of CD21 was associated with the resolution of neuroinflammation through enhancement of the MAFB-MSR1 pathway that leads to DAMP (PRX1) phagocytosis and TLR4 pathway inhibition. Red solid arrows represent promotion, red dotted arrow represents the positive correlation, green arrows represent inhibition.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (81072636 and 81473219), Sichuan Science and Technology Programs (2014JY0151 and 2018SZ0015), the Fundamental Research Funds for the Central Universities (YJ201561), Science Foundation for Excellent Youth Scholars in Sichuan Province (2017JQ0014), 111 Project of the National Ministry of Education (B18035).
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Jun-Rong Du conceptualized and designed this study. Xiao-Jia Yang, Xiao Zou, Yu-Miao Gan and Dong-Ling Liu performed this experiment.Chu Chen, Xiao-Jia Yang and Yu-Miao Gan contributed reagents and materials. Xiao Zou and Xiao-Jia Yang conducted the data analysis and prepared the draft. Jun-Rong Du rewrote the manuscript and Wei Duan assisted in the revision.
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Zou, X., Yang, XJ., Gan, YM. et al. Neuroprotective Effect of Phthalide Derivative CD21 against Ischemic Brain Injury:Involvement of MSR1 Mediated DAMP peroxiredoxin1 Clearance and TLR4 Signaling Inhibition. J Neuroimmune Pharmacol 16, 306–317 (2021). https://doi.org/10.1007/s11481-020-09911-0
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DOI: https://doi.org/10.1007/s11481-020-09911-0