Recombinant rat heat shock protein 70 (rrHSP70) may promote remyelination by regulating microglia/macrophages and oligodendrocytes in a toxin-induced demyelination animal model.

Heat shock protein 70 (HSP70) can assemble with other extracellular matrix proteins to form deoxycholate-insoluble aggregates in multiple sclerosis (MS) lesions, impairing oligodendrocyte (OLG) maturation and remyelination. However, soluble HSP70 supports myelination. HSP70 may also promote bone marrow-derived macrophages (BMDMs) toward classically and alternatively activated phenotypes, which may regulate OLG maturation. Given the roles of HSP70 in OLG maturation and in shaping microglial/BMDM phenotypes in MS lesions, we investigated how HSP70 in microglia/macrophages regulates OLG maturation in a toxin-induced demyelination model. Our results suggest that rrHSP70 may maintain HSP70 expression in microglia and BMDMs in vitro. Tandem mass tag (TMT)-labeled quantitative proteomic, post-translational modification, and phagocytosis analyses showed that rrHSP70 may induce Fc gamma R-mediated phagocytosis in microglia and BMDMs, enabling rrHSP70 engulfment and enhancing heat shock factor 1 (HSF-1) phosphorylation. Blocking or inhibiting CD45 activity reduced rrHSP70 phagocytosis and HSF-1 phosphorylation in microglia. These findings suggest that rrHSP70 may induce Fc gamma R-mediated phagocytosis in microglia and BMDMs, leading these cells to phagocytose rrHSP70 and enhance HSF-1 phosphorylation, thereby maintaining HSP70 expression in vitro. Furthermore, HSP70 levels increased during early demyelination in the animal model, suggesting that HSP70 may induce microglial/macrophage phagocytosis to remove factors that inhibit remyelination, thereby facilitating later remyelination. rrHSP70 likely promoted OLG maturation both in vivo and in vitro, as well as remyelination, possibly by enhancing myelin basic protein (MBP) expression and facilitating phosphorylated MBP redistribution. Overall, context-dependent HSP70 upregulation may be crucial for enhancing remyelination in MS lesions.