Effect of depletion of Matn3 on gene expression in mouse cerebral cortex after ischemia stroke

The role of matrilin-3 in the brain, an extracellular matrix component in cartilage, is unknown. Here, we identify matrilin-3 decreased in reactive astrocytes but unchanged in neurons after ischemic stroke in animals. Importantly, it is 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 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 cytokines transcription. Extracellular matrilin-3 binds to BMP-2, blocking BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection at least partially via suppressing astrocyte-mediated neuroinflammation. To investigate the mechanisms of matrilin-3 for suppressing glial scar formation, the RNA-seq analysis was performed in WT and Matn3 -/- mice. Mice were divided into 3 groups, sham_WT group, IR_WT group, and IR_Matn3_ko group, and three mice per group. Comparative gene expression profiling analysis of RNA-seq data for IR_WT group and sham or IR_matn3_ko group .