Fig. 3

Regulatory mechanism of efferocytosis on microglial neuroinflammation. Abnormal activation of nuclear factor kappa B (NF-κB) drives the transcriptional expression of inflammatory factors upon nuclear translocation, leading to the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). This dysregulation impairs the efferocytosis function of microglia, thereby exacerbating neuroinflammatory responses. Once mitochondrial DNA (mtDNA) is released into the cytoplasm of microglia, it can activate the STING signaling pathway, driving the translocation of NF-κB and subsequently inducing the excessive production of pro-inflammatory mediators. Exogenous stimuli can promote the sustained activation of the NF-κB pathway by activating TRAF6, further amplifying the neuroinflammatory cascade. However, the G protein-coupled estrogen receptor (GPER) can increase the phosphorylation of extracellular signal-regulated kinase (ERK), thereby blocking the nuclear translocation of NF-κB. Activation of the PI3K/Akt pathway reduces NF-κB activity, inhibiting neuroinflammation. Furthermore, ERK can activate signal transducer and activator of transcription 6 (STAT6), leading to its phosphorylation and nuclear translocation, which increases the expression of PPARγ. This, in turn, further promotes the expression and release of anti-inflammatory mediators such as arginase-1 (Arg-1) and interleukin-10 (IL-10), thereby enhancing microglial efferocytosis and facilitating neuroprotection