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  3. The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke

The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke

  • Transl Stroke Res. 2021 Dec;12(6):991-1017. doi: 10.1007/s12975-021-00888-3.
Yong-Ming Zhu  # 1,  Liang Lin  # 2,  Chao Wei  # 3,  Yi Guo 1,  Yuan Qin 1,  Zhong-Sheng Li 1,  Thomas A Kent 4,  Claire E McCoy 5,  Zhan-Xiang Wang 2,  Yong Ni 1,  Xian-Yong Zhou 1,  Hui-Ling Zhang 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, Jiangsu, China.
  • 2 The First Affiliated Hospital of Xiamen University, Xiamen, 361001, Fujian, China.
  • 3 Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shi-Zi Road, Suzhou, 215006, Jiangsu, China.
  • 4 Institute of Biosciences and Technology, Texas A&M Health Science Center, Department of Neurology, Houston Methodist Hospital, Houston, TX, USA.
  • 5 School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, 123 St Stephens Greens, Dublin 2, Ireland.
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, Jiangsu, China. zhanghuiling@suda.edu.cn.
  • # Contributed equally.
PMID: 33629276 DOI: 10.1007/s12975-021-00888-3
Abstract

Necroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth Factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar.

Keywords

Astrocyte; Glial scar; Ischemic stroke; RIP1 kinase; VEGF-D; VEGFR-3.

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