The role of HMGB1 in neuroinflammation and tissue repair: A potential therapeutic target for depression?

High mobility group protein box 1 (HMGB1), a sophisticated danger signal with pleiotropic functions, has been proved to function as a pro-inflammatory cytokine. In the central neural system (CNS), HMGB1 can stimulate microglia, the immune cell in the CNS, to release inflammatory factors and to cause chronic neurodegeneration. The evidence showed that HMGB1 can act as a pro-inflammatory cytokine mainly through its receptors like advanced glycation end product (RAGE), Toll-like 4 (TLR4), and so on. Moreover, HMGB1 contributed to the priming effects of stress-pretreatment and played a key role in neurodegeneration diseases via mediating neuroinflammation. However, the evidence also showed that HMGB1 played a role in tissue repair, with the ability to promote cell migration and proliferation, to induce the differentiation of mesenchymal stem cells (MSCs), and to regenerate spinal cord. These pleiotropic functions of HMGB1 make it possible to play a role from cell death to new life. Depression is a chronic, severe, and often life-threatening disease accompanied with impaired neurogenesis. The evidence showed that neuroinflammation played a key role in the process of depression. Depressive patients often showed a high expression of inflammatory cytokines in the blood and an activation of microglia in the brain. Meanwhile, they also showed a neuron deficit in the brain. Though they lack direct evidence linking HMGB1 with depression, the ability of HMGB1 that can function from neuroinflammation to tissue repair makes HMGB1 a promising therapeutic target of depression.