Microglia are the primary immune cells in the brain and serve as the first line of defense. In recent years, they have garnered significant attention due to their roles in immune responses and neuroinflammation. They play a crucial role in brain development by regulating neurogenesis, synaptogenesis, synapse elimination, and the formation of neuronal circuits. Furthermore, microglia possess the ability to recognize pathogens, perform phagocytosis, present antigens, and remodel synapses (DiSabato et al., 2016).

Under normal conditions, resting microglia continuously monitor the surrounding environment. Upon injury or changes in the external environment, they become activated and undergo morphological changes. Microglial cells transform from a branched form to an amoeboid shape, with cell body swelling, shortened processes, increased phagocytic activity, and elevated cytokine production. This process is referred to as microglial activation (Boche et al., 2013). Microglial activation is triggered by the recognition of pattern recognition receptors (PRRs), pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). PAMPs and DAMPs interact with microglial receptors such as Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE), thereby initiating the synthesis and release of inflammatory mediators and promoting the transmission of inflammatory signals (Liu et al., 2023). Microglial activation can occur through two main pathways: the classical M1 activation and the selective M2 activation (Jia et al., 2021). Various factors, such as cellular aging, endotoxins, inflammatory cytokines, and ROS, can drive microglia to polarize toward the M1 phenotype. M1 microglia produce pro-inflammatory factors, including IL-1β, TNF-α, IL-6, and superoxide radicals, which help clear infections and repair tissues (Takahashi et al., 2024). In contrast, M2 activation is induced by cytokines such as interleukin-4 (IL-4) and interleukin-13 (IL-13), accompanied by the release of anti-inflammatory factors like Interleukin-10 (IL-10), insulin-like growth factor-1 (IGF 1), and transforming growth factor-β (TGF-β), which promote tissue healing, regeneration, and angiogenesis, and also repair neuronal damage (Butovsky et al., 2014; Parkhurst et al., 2013; Yi et al., 2020). It promotes healing, tissue regeneration, and angiogenesis, and can inhibit or promote the repair of neuronal injury (Wang et al., 2022; Figure 1).

However, recent research has revealed that categorizing microglia solely into M1 and M2 phenotypes is an oversimplification. Through high-throughput single-cell RNA sequencing, researchers have analyzed the RNA expression patterns of over 76,000 microglial cells from mice at different developmental stages, during aging, and in response to brain injury. The study identified at least nine distinct microglial states, which vary according to development, aging, and injury (Hammond et al., 2019). Refining the classification of microglia will help to better understand the functions, signaling mechanisms, and interactions of these subtypes with other brain cells. This, in turn, could facilitate the identification of specific microglial biomarkers for assessing human health and disease states.

Activated microglia show different responses to external stimuli, which is a double-edged sword: Acutely activated microglia usually promote tissue repair by removing invading pathogens and cell debris; Sustained microglial activation causes chronic neuroinflammation, which worsens the damage and promotes disease progression. With the deepening of the research on the pathogenesis of depression, the role of microglia in the pathogenesis of depression has also been proved in large numbers, so depression is also considered to be a microglia-related disease (microgliosis) (Yirmiya et al., 2015; Wang et al., 2022; Deng et al., 2020). Here, we summarize recent research over the past 3 years on the mechanisms through which the modulation of microglial phenotype exerts anti-inflammatory and antidepressant effects. Understanding these mechanisms is crucial for identifying new directions in the treatment and drug development for depression (Table 2).

Traditionally, astrocytes have been regarded as supportive cells for neurons, playing a critical role in maintaining brain homeostasis and the normal function of neurons. As the largest cell type in the CNS, astrocytes provide energy, recycle neurotransmitters, supply neurotrophic factors, and regulate synaptic formation and elimination. They also maintain the BBB and participate in immune signaling (Colombo and Farina, 2016). When the CNS undergoes damage, such as trauma, neurodegenerative diseases, or infections, astrocytes exhibit rapid changes in gene expression, morphology, and function, a response known as astrocyte reactivity (Stoklund Dittlau and Freude, 2024). Research indicates that reactive astrocytes may have detrimental effects, such as exacerbating neuroinflammation, inhibiting synaptic sprouting, or axonal growth. However, some studies suggest that A1 and A2 reactive astrocytes have beneficial roles, including anti-inflammatory effects, neuroprotection, and BBB repair (Rupareliya et al., 2023). Compared to normal astrocytes, A1 astrocytes lose many critical functions, particularly the maintenance of synaptic activity. Furthermore, A1 astrocytes significantly upregulate substances that are harmful to synapses, such as complement cascade factors, IL-1β, TNF-α, and NO (Cong et al., 2023). In contrast, A2 astrocytes can upregulate neurotrophic factors or anti-inflammatory genes, promoting neuronal survival and growth, and playing an active role in neurorepair. Astrocytes are also responsible for the uptake and metabolism of over 90% of glutamate in the brain (Mahmoud et al., 2019). When astrocytes are deficient, excessive accumulation of glutamate in the synaptic cleft may lead to excitotoxicity and an imbalance in neuronal activity (Wang et al., 2017; Figure 1).

Recent studies, however, have shown that A1 and A2 types only represent two of the potential astrocyte transcriptomes when classifying astrocytes using multi-dimensional data and co-clustering methods. Moreover, research has found that astrocytes in a healthy brain are highly diverse and perform specific roles in different CNS circuits. Reactive astrocytes are equally heterogeneous, with RNA sequencing and microarray analysis data indicating that reactive astrocytes in various disease models exhibit distinct molecular characteristics (Henrik Heiland et al., 2019).

Current research has confirmed that astrocytes are closely involved in the pathophysiology of depression. In rodent models, chronic mild stress induces overexpression of glial fibrillary acidic protein (GFAP). Increased numbers of astrocytes have also been found in the hippocampus and medial prefrontal cortex (mPFC) of patients with major depressive disorder (Wen et al., 2024; Yuan et al., 2024). Additionally, elevated levels of glutamate have been observed in the brains and cerebrospinal fluid of depression patients, and chronic stress appears to induce brain structural atrophy by disrupting the GFAP astrocytic network (Rajkowska and Stockmeier, 2013). We summarize researches conducted over the past 3 years on the mechanisms through which astrocytes mediate antidepressant effects (Table 3). These mechanistic insights may serve as potential targets for the prevention and treatment of depression (Wang J. Y. et al., 2024).

Microglia and astrocytes play dual roles in brain diseases. They not only enhance immune responses and promote neurodegeneration, but also modulate the inflammatory responses in the central nervous system (Goshi et al., 2020). Furthermore, the interaction between astrocytes and microglia plays a critical role in neuroinflammatory responses (Olude et al., 2022).

These two types of glial cells regulate inflammation in the central nervous system through the secretion of cytokines and inflammatory mediators (Kim and Son, 2021). For example, LPS-activated microglia can induce a neurotoxic phenotype in astrocytes by secreting Interleukin-1α (IL-1α), TNF-α, and complement component C1q, triggering transcriptional responses in astrocytes that lead to the production of neurotoxic factors while inhibiting phagocytic function and the expression of neurotrophic factors (Li S. et al., 2022). Moreover, aryl hydrocarbon receptor (AHR) in microglia regulates the expression of vascular endothelial growth factor B (VEGF-B) and Transforming growth factor-α (TGF-α), further promoting the expression of pro-inflammatory genes in astrocytes, such as CCL2, IL-1β, and nitric oxide synthase 2 (NOS2) (Ge et al., 2021). The production of TNF-α enhances the release of glutamate from astrocytes, thereby increasing neuronal excitotoxicity. Studies have also shown that NF-κB signaling in microglia activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, which in turn triggers A1-type astrocytes through caspase-1 activation. A1 astrocytes secrete factors such as CCL2, C-X3-C motif chemokine ligand 1 (CX3CL1), C-X-C motif chemokine ligand 10 (CXCL10), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-1 (IL-1), which in turn activate pro-inflammatory microglia (Linnerbauer et al., 2020; Jha et al., 2019). Furthermore, the deficiency of sigma-1 receptors in astrocytes leads to the activation of the NF-κB pathway, thereby amplifying the interaction between reactive astrocytes and activated microglia, exacerbating neuroinflammation and triggering stress-induced neuronal apoptosis, ultimately resulting in depressive-like behavior in mice (Figure 2).

Increasingly, studies are concentrating on the mechanisms and effects of natural products with anti-inflammatory activities in improving depressive-like behaviors. The structural diversity and broad pharmacological effects of natural products are notable characteristics that are not commonly found in synthetic antidepressants (Dai et al., 2022). Natural products can modulate neural function through various mechanisms, such as affecting receptors or regulating immune processes, thereby achieving anti-inflammatory and antidepressant effects (Noori et al., 2022).

Compound 3C is a derivative of (+)-balasubramide, an 8-metalactam compound extracted from the yellow peel leaf of the Sri Lankan plant, which has been shown to have significant anti-inflammatory effects in microglia. Further investigation of the pharmacological activity of compound 3C showed that compound 3C could improve the depressive behavior of mice with endotoxins induced neuroinflammation by promoting the anti-inflammatory activity of microglia through adenosine 5’-monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) signaling pathway, enhancing the expression of a variety of anti-inflammatory mediators, and inhibiting the pro-inflammatory activity of microglia (Wang et al., 2018). Astragaloside IV (AS-IV) has antioxidant, anti-inflammatory, anti-hypertensive and neuroprotective effects (Abd Elkader et al., 2021). It has been reported that AS-IV may alleviate peroxisome proliferator-activated receptor γ (PPARγ)/ axis-mediated neuroinflammation and relieve depression-like behaviors in chronic restraint stress-induced and LPS-induced mice by up-regulating PPARγ expression. Baicalin, a widely used drug, has strong anti-inflammatory, anti-oxidation and anti-apoptosis activities (Song et al., 2018). Recent studies using chronic unpredictable mild stress (CUMS)-induced and endotoxin-induced depression mice have demonstrated that baicalin can improve depressive-like behavior and neuroinflammation by inhibiting the harmful overexpression of Toll-like receptor 4 (TLR4) by inhibiting the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/forkhead Box O1 (FOXO1) pathway (Guo et al., 2019). Ginsenoside Rg1 is widely reported to have a strong neuroprotective effect (Wang et al., 2023). Further evidence suggests that Rg1 may inhibit the transcriptional activity of NF-κB by increasing anti-inflammatory and inhibiting pro-inflammatory cytokines, neurotoxic mediators, pro-apoptotic proteins and microglia activation, as well as regulating mitogen activation and sirtuin 1 (SIRT1) signaling pathways. Thus, it can reduce chronic social defeat stress (CSDS) -induced hippocampal neuroinflammation and improve adult hippocampal neurogenesis, and play an antidepressant role (Jiang et al., 2020). Many previous studies have found that pinocembrin exhibit antioxidant, anti-inflammatory and neuroprotective effects both in vitro and in vivo (Li J. M. et al., 2022). Current studies have shown that Pinocembrin can reverse CUMS-induced depression-like behaviors by acting against neuroinflammation and apoptosis through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) and NF-κB signaling pathways (Wang et al., 2020). In addition, catalpol has been shown to have anti-inflammatory, anti-tumor and anti-oxidative effects (Liang et al., 2023). Recently, catalpol has been shown to improve depression-like behaviors in CUMS mice by alleviating oxidative stress-mediated NLRP3 inflammasome activation and neuroinflammation (Wang et al., 2021). Previous studies have shown that cinnamic acid can attenuate LPS-induced depression-like behaviors by reducing LPS-induced inflammation and oxidative stress, and ameliorating LPS-induced BDNF damage (Zhuo et al., 2022). In addition to the above related findings, recent studies have also found that Asperosaponin VI exerts antidepressant effects by inhibiting TLR4/NF-κB signaling pathway, inhibiting microglia-mediated neuroinflammation, down-regulating the expression of indoleamine 2, 3-dioxygenase (IDO) and normalizing abnormal glutamate transmission (Zhang et al., 2020).

By exploring the specific mechanisms and effects of these compounds in anti-inflammatory and anti-depressive effects in vivo and in vitro depression models, it lays a foundation for the pathogenesis and treatment of depression (Figure 3 and Table 4).