Inhibition of MALT1 Alleviates Spinal Ischemia/Reperfusion Injury-Induced Neuroinflammation by Modulating Glial Endoplasmic Reticulum Stress in Rats

• Main Authors: Zhang S, Yan Y, Wang Y, Sun Z, Han C, Qian X, Ren X, Feng Y, Cai J, Xia C
• Format: Article
• Language: English
• Published: Dove Medical Press 2021-09-01
• Series: Journal of Inflammation Research
• Subjects: malt1; blood-spinal cord barrier; astrocytes; microglia; endoplasmic reticulum stress; spinal cord ischemia/reperfusion injury
• Online Access: https://www.dovepress.com/inhibition-of-malt1-alleviates-spinal-ischemiareperfusion-injury-induc-peer-reviewed-fulltext-article-JIR

Shutian Zhang,1,2,* Yufeng Yan,3,* Yongze Wang,1,2 Zhaodong Sun,1,2 Chengzhi Han,1,2 Xinyi Qian,1,2 Xiaorong Ren,1,2 Yi Feng,4 Jian Cai,5 Chunmei Xia1 1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3Experimental Teaching Center of Basic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China; 5Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200240, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunmei XiaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of ChinaTel [phone]Email [e-mail] CaiDepartment of Neurology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200240, People’s Republic of ChinaEmail [e-mail]: Glial activation and the disorders of cytokine secretion induced by endoplasmic reticulum stress (ERS) are crucial pathogenic processes in establishing ischemia/reperfusion (I/R) injury of the brain and spinal cord. This present study aimed to investigate the effects of mucous-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) on spinal cord ischemia/reperfusion (SCI/R) injury via regulating glial ERS.Methods: SCI/R was induced by thoracic aorta occlusion-reperfusion in rats. The MALT1-specific inhibitor MI-2 or human recombinant MALT1 protein (hrMALT1) was administrated for three consecutive days after the surgery. Immunofluorescent staining was used to detect the localization of MALT1 and ERS profiles in activated astrocyte and microglia of spinal cord. The ultrastructure of endoplasmic reticulum (ER) was examined by transmission electron microscopy. Blood-spinal cord barrier (BSCB) disruption and noninflammatory status were assessed. The neuron loss and demyelination in the spinal cord were monitored, and the hindlimb motor function was evaluated in SCI/R rats.Results: Intraperitoneally postoperative MI-2 treatment down-regulated phos-NF-κB (p65) and Bip (ERS marker protein) expression in the spinal cord after SCI/R in rats. Intraperitoneal injection MI-2 attenuated the swelling/dilation of ER of the glia in SCI/R rats. Furthermore, MI-2 attenuated I/R-induced Evans blue (EB) leakage and microglia M1 polarization in spinal cord, implying a role for MALT1 in the BSCB destruction and neuroinflammation after SCI/R in rats. Furthermore, intrathecal injection of hrMALT1 aggravated the fragmentation of neuron, loss of neurofibrils and demyelination caused by I/R, while 4-PBA, an ERS inhibitor, co-treatment with hrMALT1 reversed these effects in SCI/R rats. hrMALT1 administration aggravated the motor deficit index (MDI) scoring, while 4-PBA co-treatment improved SCI/R-induced motor deficits in rats.Conclusion: Inhibition of MALT1 alleviates SCI/R injury-induced neuroinflammation by modulating glial endoplasmic reticulum stress in rats.Keywords: MALT1, blood-spinal cord barrier, astrocytes, microglia, endoplasmic reticulum stress, spinal cord ischemia/reperfusion injury