Matrilin-3 supports neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation
Xianyong Zhou,
Yongming Zhu,
Defei Gao,
Min Li,
Liang Lin,
Zhanxiang Wang,
Huaping Du,
Yuan Xu,
Jin Liu,
Yang He,
Yi Guo,
Shuai Wang,
Shigang Qiao,
Yingshi Bao,
Yuan Liu,
Huiling Zhang
Affiliations
Xianyong Zhou
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Yongming Zhu
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Defei Gao
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Min Li
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Liang Lin
The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China
Zhanxiang Wang
The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China
Huaping Du
Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215200, China
Yuan Xu
Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215200, China
Jin Liu
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Yang He
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Yi Guo
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Shuai Wang
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China
Shigang Qiao
Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Suzhou, Jiangsu 215301, China; Suzhou Science & Technology Town Hospital, Suzhou, Jiangsu 215163, China
Yingshi Bao
Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215200, China
Yuan Liu
Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215200, China; Corresponding author
Huiling Zhang
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, China; Corresponding author
Summary: In the brain, the role of matrilin-3, an extracellular matrix component in cartilage, is unknown. Here, we identify that matrilin-3 decreased in reactive astrocytes but was unchanged in neurons after ischemic stroke in animals. Importantly, it declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death, and glial scar, respectively, but has no direct effect on neuronal cell death. RNA sequencing demonstrates that Matn3−/− mice display an increased inflammatory response profile in the ischemic brain, including the nuclear factor κB (NF-κB) signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokine transcription. Extracellular matrilin-3 binds to BMP-2, blocking the BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection, at least partially, by suppressing astrocyte-mediated neuroinflammation.
