Mutant erythropoietin enhances white matter repair via the JAK2/STAT3 and C/EBPβ pathway in middle-aged mice following cerebral ischemia and reperfusion.

Abstract

Previous studies have indicated that EPO maintains the M2 microglia phenotype that contributes to white matter repair after ischemic stroke in young mice (2 months old). However, the underlying mechanisms that regulate microglial polarization are poorly defined. This study investigated the neuroprotective effects of nonerythropoietic mutant EPO (MEPO) on white matter and the underlying mechanism in middle-aged (9-month-old) male mice following cerebral ischemia. Middle-aged male C57 BL/6 mice were treated with MEPO (5000 IU/kg) or vehicle after middle cerebral artery occlusion (MCAO) and reperfusion. The specific inhibitor AG490 was used to block the JAK2/STAT3 pathway. Neurological function was assessed by beam walking and adhesive removal tests. Immunofluorescence staining and western blotting were used to assess the severity of white matter injury, phenotypic changes in the microglia and the expression of the signaling molecules. MEPO significantly improved neurobehavioral outcomes, alleviated brain tissue loss, and ameliorated white matter injury after MCAO compared with the vehicle group. Moreover, MEPO promoted oligodendrogenesis by shifting microglia toward M2 polarization by promoting JAK2/STAT3 activation and inhibiting the expression of C/EBPβ at 14 days after cerebral ischemia-reperfusion. However, the MEPO's effect on microglial M2 polarization and oligodendrogenesis was largely suppressed by AG490 treatment. Collectively, these data indicate that MEPO treatment improves white matter integrity after cerebral ischemia, which may be partly explained by MEPO facilitating microglia toward the beneficial M2 phenotype to promote oligodendrogenesis via JAK2/STAT3 and the C/EBPβ signaling pathway. This study provides novel insight into MEPO treatment for ischemic stroke.

• Authors: Rongliang Wang, Sijia Zhang, Zhenhong Yang, Yangmin Zheng, Feng Yan, Zhen Tao, Junfen Fan, Haiping Zhao, Ziping Han, Yumin Luo
• Journal: Experimental neurology (Exp Neurol) Vol. 337 Pg. 113553 (03 2021) ISSN: 1090-2430 [Electronic] United States
• PMID: 33309747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• CCAAT-Enhancer-Binding Protein-beta
• Epo protein, mouse
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• Erythropoietin
• Jak2 protein, mouse
• Janus Kinase 2
• Steroid Isomerases
• EBP protein, human

Topics

• Animals
• Behavior, Animal (drug effects)
• Brain Ischemia (drug therapy, pathology)
• CCAAT-Enhancer-Binding Protein-beta (drug effects)
• Cell Polarity (drug effects)
• Erythropoietin (genetics, therapeutic use)
• Janus Kinase 2 (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects)
• Mutation
• Oligodendroglia (drug effects)
• Recovery of Function
• Reperfusion Injury (drug therapy, pathology)
• STAT3 Transcription Factor (drug effects)
• Signal Transduction (drug effects)
• Steroid Isomerases
• Tyrphostins (pharmacology)
• White Matter (pathology)