Depression is a serious mental disorder with a high incidence rate (McCarron et al., 2021; Monroe and Harkness, 2022). Depression is characterized by persistently low mood, delayed thinking, and reduced volitional activity (Wang et al., 2022). Depression causes a heavy burden of disease and is an important cause of physical disability (Greenberg et al., 2021; Monroe and Harkness, 2022). Neuroinflammation refers to inflammatory reactions that occur in the central nervous system (CNS) and is caused by various pathological injuries (Leng and Edison, 2021; Maccioni et al., 2018). Microglia are the main functional cells that mediate neuroinflammation in the CNS (Liu et al., 2022; Rodríguez et al., 2022), and monitor and clear dead cells, pathogenic proteins, and other pathological particles from the CNS (Colonna and Butovsky, 2017; Rodríguez et al., 2022). Resting microglia exhibit multiple branches, long branches, and small cell bodies (Fernández-Mendívil et al., 2021). Microglia have migratory properties in the CNS (Fu et al., 2014; Yu et al., 2022). When damage or abnormalities occur in specific parts of the brain, the surrounding microglia move to the pathological site and resting microglia are activated (Fu et al., 2014; Yu et al., 2022). Activated microglia exhibit amoebic morphology with fewer and shorter branches, and larger cell bodies (Cao et al., 2021; Fernández-Mendívil et al., 2021). Activated microglia can be divided into 2 types: M1 and M2. M1 type microglia release pro-inflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) (Orihuela et al., 2016; Wang et al., 2022). M2 type microglia release anti-inflammatory factors, including IL-4, IL-10, and transforming growth factor-beta (TGF-β) (Orihuela et al., 2016; Wang et al., 2022).

The occurrence and development of depression are closely associated with neuroinflammation (Beurel et al., 2020; Cao et al., 2021; Guo et al., 2023; Wang et al., 2022; Zhang et al., 2018). Administration of an aluminum chloride solution to rats resulted in depression and upregulated the expression of TNF-α and IL-1β in the hippocampus (Zhang et al., 2020). Minocycline inhibits microglial polarization. Subcutaneous injection of lipopolysaccharide (LPS) into newborn male mice resulted in depression- and anxiety-like behaviors in adulthood, and upregulated TNF-α and IL-1β expression in the hippocampus; however, these effects were reversed by oral administration of minocycline solution, suggesting that early immune activation-mediated neuroinflammation led to depression (Majidi et al., 2016). Compared with traumatic brain injury (TBI) alone, establishing a TBI model after intraperitoneal injection of LPS increased depressive-like behavior and upregulated the expression of TNF-α and IL-1β messenger RNA in the brain (Fenn et al., 2014). Knockout of microglial glutaminase 1 significantly reduced IL-1β, IL-6, and TNF-α expression in the prefrontal cortex and significantly reduced the immobility time of mice in the forced swimming test (FST) induced by LPS, indicating that neuroinflammation was associated with depressive behavior (Ji et al., 2022). Berberine reduced corticosterone-induced depression-like behavior in mice by inhibiting NOD-like receptor protein 3 signaling pathway-mediated neuroinflammation (Qin et al., 2023). Intraperitoneal injection of LPS induced depression and upregulated the expression of IL-6 and TNF-α in the hippocampus (Li et al., 2021).

Histone methylation is also associated with inflammatory diseases (Li et al., 2022; Lin et al., 2022; Wang et al., 2020). Protein arginine methyltransferase (PRMT) 2 is a type I PRMT enzyme that catalyzes the production of asymmetric dimethylarginine (ADMA) (Cura and Cavarelli, 2021). Studies have reported that PRMT2 regulates the inflammatory response (Vhuiyan et al., 2017; Zhu et al., 2021). Knockdown of PRMT2 upregulated the expression of IL-6 and TNF-α in mouse lungs (Dalloneau et al., 2011). Knockout of PRMT2 in mouse embryo fibroblasts activated nuclear factor-κB (NF-κB), suggesting that PRMT2 inhibits the activity of NF-κB (Ganesh et al., 2006). Angiotensin II (AngII) significantly upregulated the expression of IL-6 and IL-1β in vascular smooth muscle cells; however, the overexpression of PRMT2 reversed the production of pro-inflammatory factors induced by AngII (Zeng et al., 2018). LPS induces macrophages to release the pro-inflammatory factor IL-6, and knockout PRMT2 of in macrophages significantly upregulates the expression of IL-6 induced by LPS, indicating that PRMT2 has anti-inflammatory effects (Vurusaner et al., 2022). Arg 1 is a marker of M2 polarization in macrophages. IL-4 treatment upregulates the expression of arginase 1 (Arg1) in macrophages, and PRMT2 knockout in macrophages significantly reduces the expression of Arg1 induced by IL-4, indicating that PRMT2 promotes M2 polarization in macrophages (Vurusaner et al., 2022). PRMT2 increased interferon (IFN) -β expression through activation of toll-like receptor signaling (Wang et al., 2021b). In summary, PRMT2 exerts anti-inflammatory effects. Notably, a previous study predicted that PRMT2 may be associated with the occurrence and development of depression (Orru et al., 2019), and our experimental results have validated this hypothesis. PRMT2 overexpression in the hippocampus exerts anti-neuroinflammatory effects and promotes the conversion of microglia from the pro-inflammatory M1 to anti-inflammatory M2 type, facilitating the restoration of a normal inflammatory state in the hippocampus. Combined with the detection of depressive behavior, our results demonstrate that PRMT2 overexpression may be used to prevent or treat depression through an anti-neuroinflammatory mechanism.