Chromogranin B acts as a neuronal paracrine factor to trigger oligodendrocyte apoptosis

Various soluble factors, such as inflammatory cytokines and autoantibodies secreted by activated microglia, macrophages, and astrocytes, are known to promote death of oligodendrocyte (OL) lineage cells, including OLs and OL precursor cells (OPCs), in the central nervous system during demyelination of multiple sclerosis. However, the role of factors secreted by neurons in OL lineage cell death remains underexplored. Chromogranin B (Chgb), a critical protein for secretory granule formation in neuroendocrine cells, is also specifically expressed and secreted from neurons. In this study, we investigated the effect of extracellular Chgb on OL lineage cells. We found that treatment with recombinant mouse or human Chgb significantly reduced the population of both mature OLs and OPCs by inducing apoptosis. This Chgb-induced apoptosis was effectively suppressed by an anti-Chgb antibody. Furthermore, in neuron-OPC/OL cocultures, endogenous Chgb secreted by neurons similarly promoted OL apoptosis, an effect that was also neutralized by the anti-Chgb antibody. Collectively, these results identify Chgb as a neuronal paracrine factor that triggers apoptotic death in OL lineage cells. Our findings provide new insights into the regulation of OL lineage cell death by neuronal secretion factors.