Molecular insights into the therapeutic promise of targeting HMGB1 in depression

Depression is a common psychiatric disorder, the exact pathogenesis of which is still elusive. Studies have proposed that immunity disproportion and enhancement in proinflammatory cytokines might be linked with the development of depression. HMGB1 (High-mobility group box (1) protein has obtained more interest as an essential factor in inherent immune reactions and a regulating factor in various inflammation-related diseases. HMGB1 is a ubiquitous chromatin protein and is constitutively expressed in nucleated mammalian cells. HMGB1 is released by glial cells and neurons upon inflammasome activation and act as a pro-inflammatory cytokine. HMGB1 is a late mediator of inflammation and has been indicated as a major mediator in various neuroinflammatory diseases. Microglia, which is the brain immune cell, is stimulated by HMGB1 and released inflammatory mediators and induces chronic neurodegeneration in the CNS (central nervous system). In the current review, we aimed to investigate the role of HMGB1 in the pathogenesis of depression. The studies found that HMGB1 functions as proinflammatory cytokines primarily via binding receptors like RAGE (receptor for advanced glycation end product), TLR2 and TLR4 (Toll-like receptor 2 and 4). Further, HMGB1 added to the preparing impacts of stress-pretreatment and assumed a major function in neurodegenerative conditions through moderating neuroinflammation. Studies demonstrated that neuroinflammation played a major role in the development of depression. The patients of depression generally exhibited an elevated amount of proinflammatory cytokines in the serum, microglia activation and neuronal deficit in the CNS.