Toll-like Receptor 2 Exerts Oligodendrocyte Protection in White Matter Stroke Through Downstream NF-κB-cIAP2

Ischemic white matter stroke (WMS) is a substantial proportion of ischemic stroke, a major contributor to vascular dementia and a common pathologic finding in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Despite its significance, disease-specific treatment strategies for WMS are not available as of now, making WMS a major unmet medical need. The principal pathomechanism of WMS is the death of oligodendrocytes (OLs) and ensuing demyelination, therefore the prevention of ischemic OL death is crucial to overcoming WMS. In the present article, we delineate the signaling pathway of an OL-protective mechanism that rescues ischemic OL death, which is initiated by Toll-like receptor 2 (TLR2). Through a series of in vitro experiments with primary OLs, utilizing the TLR2 agonist, oxygen-glucose deprivation, chemical inhibitors, siRNA, and overexpression vectors for candidate signaling proteins, we uncovered that the mitogen-activated protein kinase p38 pathway and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway are necessary and sufficient factors for the TLR2-mediated OL protection. In detail, the p38 pathway took action through the NF-κB pathway to exert its protective functions, and the final downstream effector was cellular inhibitor of apoptosis protein 2 (cIAP2). We validated the presence of the TLR2-NF-κB-cIAP2 axis in an unbiased search of the OL transcriptome, in an animal model of internal capsule WMS, and in human OLs. In conclusion, we demonstrate that the TLR2-NF-κB-cIAP2 axis is an OL-protective mechanism against WMS, which may be a valuable therapeutic target for drug development/repositioning to address the unmet medical need.