Pentraxin 3 promotes microglial M2 polarization and excitatory synapse formation in the hippocampus in depression

Depression is a prevalent mental illness that significantly impairs individuals' overall quality of life and physical well-being. However, the pathological mechanisms of depression remain unclear, and effective treatment strategies are urgently needed. Pentraxin 3 (PTX3), a long pentraxin protein, plays a significant role in various pathological conditions, including infections, immune responses, and tissue repair. In this study, we collected serum from patients with depression and established both animal and cell models of depression. We found that PTX3 expression was significantly reduced in both the serum of patients with depression and the hippocampus of chronic unpredictable mild stress (CUMS) mice. PTX3 supplementation markedly improved depressive-like behavior in CUMS mice and promoted microglial M2 polarization. In the LPS-induced BV2 cell model, PTX3 overexpression facilitated microglial M2 polarization via activation of the CREB/CEBPb axis. Additionally, PTX3 enhanced fibroblast growth factor 22 (FGF22) expression and excitatory synapse formation in the CA3 region of the hippocampus in CUMS mice. In the dexamethasone (DXM)-treated SH-SY5Y cell model, PTX3 overexpression increased SPI1 expression, elevated FGF22 transcriptional activity, and promoted the expression of excitatory synapse-related proteins PSD95 and VGLUT1. In summary, our study demonstrates that PTX3 promotes microglial M2 polarization and excitatory synapse formation in the hippocampus, suggesting potential antidepressant effects and providing theoretical support for considering PTX3 as a therapeutic target for depression.