Regulation of the microglial polarization for alleviating neuroinflammation in the pathogenesis and therapeutics of major depressive disorder.

Major depressive disorder (MDD), as a multimodal neuropsychiatric and neurodegenerative illness with high prevalence and disability rates, has become a burden to world health and the economy that affects millions of individuals worldwide. Neuroinflammation, an atypical immune response occurring in the brain, is currently gaining more attention due to its association with MDD. Microglia, as immune sentinels, have a vital function in regulating neuroinflammatory reactions in the immune system of the central nervous system. From the perspective of steady-state branching states, they can transition phenotypes between two extremes, namely, M1 and M2 phenotypes are pro-inflammatory and anti-inflammatory, respectively. It has an intermediate transition state characterized by different transcriptional features and the release of inflammatory mediators. The timing regulation of inflammatory cytokine release is crucial for damage control and guiding microglia back to a steady state. The dysregulation can lead to exorbitant tissue injury and neuronal mortality, and targeting the cellular signaling pathway that serves as the regulatory basis for microglia is considered an essential pathway for treating MDD. However, the specific intervention targets and mechanisms of microglial activation pathways in neuroinflammation are still unclear. Therefore, the present review summarized and discussed various signaling pathways and effective intervention targets that trigger the activation of microglia from its branching state and emphasizes the mechanism of microglia-mediated neuroinflammation associated with MDD.