The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms

Abstract

Major depressive disorder is a prevalent mental disorder, yet its pathogenesis remains poorly understood. Accumulating evidence implicates dysregulated immune mechanisms as key contributors to depressive disorders. This review elucidates the complex interplay between peripheral and central immune components underlying depressive disorder pathology. Peripherally, systemic inflammation, gut immune dysregulation, and immune dysfunction in organs including gut, liver, spleen and adipose tissue influence brain function through neural and molecular pathways. Within the central nervous system, aberrant microglial and astrocytes activation, cytokine imbalances, and compromised blood-brain barrier integrity propagate neuroinflammation, disrupting neurotransmission, impairing neuroplasticity, and promoting neuronal injury. The crosstalk between peripheral and central immunity creates a vicious cycle exacerbating depressive neuropathology. Unraveling these multifaceted immune-mediated mechanisms provides insights into major depressive disorder’s pathogenic basis and potential biomarkers and targets. Modulating both peripheral and central immune responses represent a promising multidimensional therapeutic strategy.

Introduction

Major depressive disorder(MDD) is a prevalent mental disorder characterized by symptoms including low mood, diminished interest, slowed thinking, poor appetite and sleepless. According to the World Health Organization (WHO), more than 280 million people worldwide currently suffer from MDD, accounting for 3.8% [1] of the global population. MDD is marked by its limited recovery rate and high suicide rate, and projected to become the leading cause of global disease burden by 2030. The pathogenesis of MDD remains unclear, and specific experimental diagnostic markers are not yet identified. Current clinical treatments for MDD primarily focus on medication-based approaches and psychotherapy. Medication typically includes SSRIs, SNRIs, MAOIs, TCAs and anesthetics like ketamine. However, antidepressants face challenges such as slow onset of action, wide individual variation, and inconsistent long-term efficacy. Thus, unraveling the pathogenesis is essential for advancing the diagnosis and treatment of MDD.

Inflammation plays an important role in the pathophysiology of MDD. Patients with chronic inflammatory diseases have an increased risk of MDD [2], which is associated with immune dysfunction and the accumulation of inflammatory factors [3]. Immune cells and associated cytokines interact with the brain through neurological, endocrine, and immune pathways, affecting mood, cognition, and behavior. Patients with MDD also exhibit abnormalities in immune activity [4]. Both peripheral and central immune mechanisms contribute to the onset and progression of MDD through a complex interplay of neuroinflammatory processes. Peripherally, systemic inflammation with elevated cytokines, gut immune dysregulation and dysbiosis, immune dysfunction in liver, spleen and adipose tissue generate inflammatory signals impacting the brain. Neural connections also facilitate bidirectional propagation of peripheral and central inflammation [5–8]. Centrally, the infiltration of peripheral inflammatory mediators, aberrant microglial and astrocytic activation, imbalance of pro/anti-inflammatory cytokines, and subsequent neuroinflammation disrupts neurotransmission, impairs neuroplasticity, and causes neuropathological changes inside the brain [4, 9, 10]. This multifaceted interaction between peripheral immune dysregulation and central neuroinflammation forms the immunological basis of MDD pathogenesis.

In this review, we explore the intricate interactions between peripheral and central immune mechanisms in the pathogenesis of MDD. By examining the role of neuroinflammation and immune dysregulation, we aim to provide a comprehensive understanding of how these processes contribute to depressive symptoms. This exploration highlights potential biomarkers and therapeutic targets, paving the way for more effective, multidimensional treatment strategies for MDD.

Peripheral immune and interactions between peripheral and central immune mechanisms

Systemic inflammation

Numerous factors are intricately associated with the pathogenetic mechanism of MDD. Among these, the systemic inflammatory response elicited by chronic stress, infection, and stress - inducing events occupies a pivotal position [11, 12]. Systemic inflammatory cytokines, mainly including TNF-α, IL-1β, and IL-1 serving as significant indices reflecting the systemic inflammatory status, furnish objective and indispensable criteria for the assessment of the degree of immune activation in patients with MDD [13].

The release of TNF-α into the bloodstream triggers the activation the immune system and sevretion of other cytokines, such as IL-6, IL-1β, and IL-8, this process exhibits an inherent congruence with relevant reactions within the central nervous system [14]. TNF-α enhances IDO activity, shunting tryptophan metabolism towards kynurenine (KYN) pathway, reducing serotonin synthesis [15] and affecting mood and cognitive function [16]. Concurrently, KYN and its derivatives can activate microglia, thereby triggering a neuroinflammatory response [17]. Moreover, peripheral KYN pathway markers can extend to the cerebrospinal fluid, directly affecting MDD at the central level. Clinically, peripheral TNF-α induces depressive-like symptoms and attenuates brain reward function [18, 19], while anti-TNF-α drugs show efficacy in treating refractory MDD [20].

Under the stimulation of chronic stress, monocytes and macrophages are activated, subsequently releasing IL-1, IL-1β and IL-6, which act in concert to induce a systemic immune response [10, 21]. IL-1 promotes the activation of the hypothalamic- pituitary-adrenal (HPA) axis [22] thus precipitate in the onset of MDD. Additionally, IL-1β can stimulate CD4 + T cells to differentiate into Th17 cells [23], leading to an imbalance in the Th17/Treg ratio and modifying the peripheral immune microenvironment [24]. In this state, peripheral inflammatory factors permeate the BBB, interferere with neurotransmitter metabolism and neural signal transmission, ultimately resulting in depressive and anxiety-like behaviors in chronic unpredictable mild stress (CUMS) mouse model [25]. Clinical investigations have also revealed a significantly elevated serum IL-6 level in patients with MDD [26–29].

Conversely, Treg differentiation factor IL-2 was decreased in MDD patients [30]. Low-dose IL-2 mitigated depressive and anxiety behaviors in CUMS mice by rebalancing hippocampal Th17/Treg ratio, modulating Foxp3+/RORα and IL-6/TGF-β, and suppressing M1 microglial and A1 astrocytic activation [31]. A phase II clinical randomized controlled study has demonstrated that IL-2 enhances the response to antidepressant treatment [32].

Stress - related events can trigger an acute stress response, resulting in a transient activation of the peripheral immune system. The level of C - reactive protein (CRP) is closely correlated with the intensity of the inflammatory response within the body, and an elevation in its level implies an enhanced inflammatory condition. Multiple studies have corroborated that the CRP level is elevated in depressive patients [33–35]. However, no significant disparity in the CRP level has been observed between patients with first-episode major depressive disorder (FEMD) and those with recurrent major depressive disorder (RMD) [36, 37].

The interaction between central and peripheral immune mechanisms is facilitated through both cytokine signaling and neural pathways. Systemic inflammatory cytokines can increase the permeability of the blood-brain barrier, allowing inflammatory mediators to enter the brain, acting on brain immune cells to trigger a neuroinflammatory response. These cytokines also diffuse along nerve fibers to areas in prefrontal cortex, hippocampus, and amygdala, act directly on neurons, initiating NF-κB and JAK-STAT signal transduction pathways [38, 39]. This affects neurotransmitter production, neuroplasticity, and neuronal survival [40].

Gut immune and gut-brain axis

The intestine is not only essential for digestion and nutrient absorption but also represents the largest compartment of the immune system. With a vast number of immune cells and microbial communities, the gut interacts through neural, endocrine, and immune pathways with central nervous system and brain function, known as the gut-brain axis. Gut immunity and gut-brain axis are emerging as a critical component in the development and progression of MDD [41].

Immune responses in the gut elevate the levels of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β which trigger systemic inflammation [42], alter brain function by affecting neurotransmitter systems, neuroplasticity, and the integrity of the blood-brain barrier and consequently induce MDD [43]. The activation of intestine immune system also increases gut permeability, allowing endotoxins like LPS to enter the bloodstream and promote neuroinflammation, further exacerbating depressive symptoms [44].

In addition, gut microbiota plays a potential regulatory role in MDD. Studies have indicated patients with MDD are disturbed by both the composition and amount of gut microbiome [45, 46]. Gut microbiota also participates in the development of MDD through interactions with immune cells. A mouse model study reveals Lactobacillus species involved in colonic IL-17-producing γδ T cells differentiation and contributes to MDD by their meningeal accumulation [47].

Moreover, metabolites and neuroactive substances produced by gut microbiota are involved in the pathophysiology of MDD by regulating immune responses and neural functions. Short-chain fatty acids (SCFAs) modulate central activity through fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3) [48]. SCFAs can directly target microglia without passing through receptors and exert inhibitory effects on histone deacetylase (HDAC) activity, nuclear factor-kappa B (NF-κB) activity, and lipopolysaccharide (LPS)-induced neuroinflammation [49]. Moreover, some SCFAs can cross the blood-brain barrier (BBB) by diffusion [50, 51] or via monocarboxylate transporter proteins located on endothelial cells and inhibit inflammatory responses [52]. Neuroactive substances produced by gut microbiota, such as serotonin (5-HT) and gamma-aminobutyric acid (GABA), are also involved in the regulation of mood and behavior. In depressive states, the gut microbiota induce alterations in 5-HT [53–55]and GABA [56, 57] and activate the vagus nerve (VN), passing inflammation signal to the brainstem and hippocampus, exacerbating depressive conditions [58]. Additionally, gut hormones also regulate physiological functions and cognitive processes in the brain. GLP-1 secreted by intestinal enteroendocrine L-cells bind with receptors distributed in the hippocampus and hypothalamus, participating in learning, memory, and emotional regulation [59]. Research demonstrate GLP-1 receptor agonists can alleviate depressive symptoms by inhibiting the release of pro-inflammatory cytokines and reducing neuroinflammation, suggesting potential applications of gut hormones in the treatment of MDD [60]. Studies indicate that cholecystokinin(CCK) secreted by secretory cells in the mucosal lining of the small intestine play a role in synaptic plasticity changes related to learning and memory [61]. In CSDS-induced depressive mouse models, excitatory synaptic transmission in the CCKBLA-D2NAc glutamate aversion circuit is significantly enhanced, inhibition of this circuit can effectively overcome depressive symptoms [62]. These molecules mediate bidirectional communication between the gut and the brain, revealing key links in the pathogenesis of MDD.

Pathological changes in MDD in turn contribute to dysbiosis by altering the gut environment [63, 64]. Empirical evidence from clinical studies reveals that individuals afflicted with MDD demonstrate heightened levels of Bacteroidaceae, Desulfovibrionaceae, and Enterococcaceae, in contrast to individuals with robust health [65]. This imbalance in microbial composition facilitates the overproduction of pro-inflammatory cytokines, including TNF-α [66, 67], thereby intensifying the inflammatory response within the gut.

Liver immune

The liver is a multifunctional organ, performing critical physiological functions such as immunity, metabolism, and detoxification. Changes in its structure and function can impact brain activity [68, 69]. Studies have found that mood disorders are prevalent among patients with chronic liver disease [70], suggesting that alterations in liver structure and function may trigger or exacerbate MDD.

As liver function declines, neurotoxic compounds accumulate in the body, leading to elevated blood ammonia levels. Once ammonia enters the brain through the bloodstream, it is taken up by astrocytes and metabolized into glutamine, which activates NMDA receptors. This activation results in intracellular calcium overload, affecting synaptic function and consequently, brain function [71, 72]. Elevated levels of ammonia and glutamate also promote microglial activation, leading to the release of inflammatory cytokines and the induction of neuroinflammation, ultimately contributing to the onset of MDD [73].

In pathological states, the number of immune cells in the liver and their production of inflammatory cytokines increase. These cytokines can enter the brain via neuroendocrine pathways or the bloodstream [42], altering the permeability of the BBB and inducing neuroinflammation, which affects neurotransmission and neuronal function, thereby triggering or worsening depressive symptoms [74].

Beyond directly impacting brain function, the liver can influence the brain through the gut. The liver, gut, and brain form a communication network known as the gut-liver-brain axis [75]. The liver can alter the composition and quantity of gut microbiota and their metabolites, which, through the VN or activation of the hypothalamic-pituitary-adrenal (HPA) axis, can modify neural signals in various brain regions. These changes affect reward, motivation, mood, and stress responses [76, 77], thereby promoting the development of MDD.

Traumatic brain injury induces alterations in cerebral lipids, with lysophosphatidyl choline (LPC) and cholesterol esters (CE) being the most impacted lipid families in the hippocampus. Concurrently, it perturbs lipid metabolism and inflammatory markers in the liver, exacerbating hepatic inflammation [78]. Clinical studies have revealed fluctuations in leptin levels among depressed patients [79]. Leptin mitigates hepatic lipid levels by augmenting the secretion of triglycerides and diminishing lipogenesis [80], thereby alleviating inflammation triggered by lipid overload and lipotoxicity [81].

Spleen immune

The spleen, the largest lymphatic organ in the human body, performs crucial functions in immunity, hematopoiesis, and inflammation. With the physical function of filtering pathogens and abnormal cells from the blood, spleen facilitate interactions between antigen-presenting cells (APCs) and homologous lymphocytes [82]. Zhang X et al. have demonstrated a direct connection between CRH neurons and the splenic nerve, which regulates adaptive immunity, providing further evidence of a direct link between MDD and immune organs [83].

Further studies reveal that imbalance in regulatory B cells and plasma cells cause increased psychosocial stress. Splenic-derived B cells may influence behavior by modulating meningeal myeloid cell activation and meningeal interferon responses leading to MDD [84]. Additionally, a clinical study showed that high levels of CD8 + T cells can induce MDD [85]. Repeated stimulation of neurons expressing D1 receptors in the nucleus accumbens of tumor-implanted mice significantly increases the number of CD8 + T cells in the spleen [86]. Therefore, inhibiting the exhaustion of splenic CD8 + T cells and improving immune system function may become novel therapeutic targets for treating MDD.

Research indicates that corticosterone (CORT)-induced depressive-like mice exhibited impaired splenic function, immunity, and differential expression of genes and brain/splenic proteins, suggesting an interplay between splenic immune dysregulation and MDD pathogenesis [87]. As was shown in mouse model, stimulation of the ventral tegmental area of the brain, part of the brain’s reward circuitry, boosted splenic activity and consequently enhanced the adaptive immune response [88]. Moreover, under chronic stress, there is an escalation in the secretion of catecholamines [89], which, upon interaction with α and β adrenergic receptors in the spleen, can precipitate a reduction in splenic volume and induce immunosuppression [90, 91].

Adipose tissue immune

In addition to the liver, gut, and spleen, adipose tissue also plays a role in the development of MDD by regulating brain function. Adipocytes secrete cytokines such as TNF-α, IL-6, and chemokine MCP-1, leading to the accumulation of inflammatory cells in adipose tissue and creating a chronic inflammatory environment [92]. Studies have shown that individuals with obesity have higher levels of free fatty acids and immune cells compared to healthy individuals. These substances cause abnormal proliferation of hypothalamic microglia, subsequently affecting the functions of the hippocampus, amygdala, and reward centers [93], regions whose dysfunction is closely associated with the onset of MDD. Furthermore, dietary studies indicate that a high-fat diet can affect synaptic plasticity, insulin signaling, and corticosterone levels, thereby induce MDD [94].

Neural networks

Recently, emerging evidence suggested that neural networks connecting the brain with key peripheral immune organs influence both immunological responses and depressive behaviors [95], mainly through vagus nerve (VN) and sympathetic nervous system [96, 97].

Bone marrow receives dense sympathetic innervation [98] from PVN, medulla and VLM, these fibers suppress expression of CXCL1233 in the bone marrow, inhibits hematopoiesis, retains neutrophils and monocytes [99]. Neurons from NTS, DMV, and PVN, innervate the spleen. These neural connections influence splenic macrophages and T cells, modulating cytokine production and systemic inflammation. Restraint stress activates the cholinergic pathway via the sympathetic system, triggering anti-inflammatory programs in splenic cells [100, 101]. Neural circuits connecting the brain to the liver involve both sympathetic and parasympathetic pathways [102]. Hypothalamic regions, such as the PVN, and brainstem nuclei innervate the liver [103], regulating hepatic glucose production, lipid metabolism, and immune responses [104]. Stress-induced activation of these pathways can lead to hepatic inflammation, macrophage infiltration and metabolic syndrome, conditions frequently associated with MDD [105, 106]. Neurons in the arcuate nucleus (ARC) and PVN project to adipose tissue, influencing lipolysis, glucose metabolism, and immune cell activity within the adipose tissue, through sympathetic and parasympathetic pathways. Dysregulation of these pathways promoting inflammation and metabolic disturbances that are often comorbid with MDD.

The vagus nerve is the primary neural conduit linking the gut to the brain. Alterations in vagal tone can affect gut permeability and microbiota composition, leading to immune activation and production of pro-inflammatory cytokines [107]. Within the gut, the neural signals relayed by the brain are received by the enteric nervous system, consisting of approximately 2 to 6 million neurons, glia and extrinsic ganglia [108]. ENS system play a crucial role in maintaining gut homeostasis and preventing excessive immune activation [109], and contribute significantly to the progression of MDD by mediating the exacerbation of intestinal inflammation induced by chronic stress [110].

Vagus nerve stimulation (VNS) has been explored as a therapeutic intervention for MDD, highlighting its potential to modulate immune responses and improve mood. VNS can activate α7 nicotinic acetylcholine receptors, reducing TNF-α production induced by LPS in microglia, restoring balance in the immune system, thus providing neuroprotection [111]. This therapeutic approach underscores the importance of the vagus nerve in the neural regulation of immune functions and its potential in treating MDD.

In conclusion, neural networks linking the CNS to peripheral immune organs are integral to the bidirectional communication between the brain and the immune system. Neural signals potentially precipitate in MDD by increasing circulating immune cell numbers, altering immune cell chemotaxis, or making them more responsive to systemic inflammatory signals.

HPA axis

Stress significantly impacts the immune response and the pathological process of MDD through the HPA axis. The HPA axis regulates physiological functions by affecting hormone production and the activity and distribution of immune cells [112].

Patients with MDD typically exhibit increased secretion of adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce more glucocorticoids (GCs). Under chronic stress, elevated blood GC levels and reduced GR expression impair the normal feedback regulation of GRs. This results in persistent hyperactivity of the HPA axis, which maintains high GC levels [113] and upregulates inflammatory pathways, triggering an inflammatory response in hippocampal cells [114]. It also activates microglia [115], leading to neuroinflammation and persistent depressive symptoms. Studies have shown that using GR antagonists, such as mifepristone, can modulate cortisol and ACTH levels and improve clinical manifestations in depressed patients [116, 117].

Both chronic stress stimuli and peripheral inflammatory states are capable of leading to sustained activation of the hypothalamic-pituitary-adrenal axis (HPA axis), resulting in increased secretion of stress hormones such as cortisol. Cortisol directly promotes the release of pro-inflammatory cytokines and inhibits the synthesis and release of serotonin, dopamine, norepinephrine and anti-inflammatory cytokine IL-10. This imbalance of cytokines and changes in neurotransmitters further promote the spread of inflammatory responses throughout the body, leading to depressed mood, anxiety, and sleep disturbances. At the same time, cortisol can affect the balance of neurotransmitters and neuronal plasticity in the prefrontal cortex, hippocampus, and amygdala [118].

In conclusion, peripheral inflammatory mediators are capable of traversing the blood-brain barrier and entering the brain, where they activate microglia and astrocytes, eliciting a neuroinflammatory response. Functional alterations in immune organs, including the gut, liver, spleen, and adipose tissue, can also influence brain activity, leading to aberrations in neurotransmitter metabolism and neuronal damage. Neural networks, including the vagus nerve and sympathetic nervous system, establish connections between peripheral immune organs and the brain, modulating immune responses and depressive behaviors. Furthermore, stress can impact the hypothalamic-pituitary-adrenal (HPA) axis, altering hormone levels and cytokine balance, ultimately triggering a systemic inflammatory reaction that manifests as depressive symptoms. These mechanisms are illustrated in Fig. 1.

Fig. 1.

Peripheral immune and interactions between peripheral and central immune mechanisms

The figure shows the complex interaction between peripheral and central immune mechanisms during inflammation. Inflammatory cells in adipose tissue secrete cytokines (IL − 6, MCP − 1, TNF - α), activating sympathetic nerves, the HPA axis, and bone marrow, causing the release of hormones (CRH, ACTH, cortisol). Inflammatory cytokines increase brain glutamine, activate the vagus nerve, and elevated blood ammonia from liver metabolism damages the blood - brain barrier. Also, cytokines, bile acid, and immune cells disrupt the intestinal barrier, increasing bacterial translocation and the inflammatory response. This activates immune cells (B cells, plasma cells, neutrophils, monocytes) and cause the releasing of inflammatory mediators (cytokines, GABA, GLP − 1, G - CSF). The figure emphasizes the complex interaction involving various systems, cytokines, hormones, and neurotransmitters in inflammatory conditions

Central immune mechanisms in MDD

As discussed, peripheral immune activation affect the central nervous system through various pathways, precipitating and exacerbating depressive symptoms. Moreover, once peripheral inflammatory molecules gain access to the brain, they inevitably activate the resident immune cells of the central nervous system, initiating a cascade of neuroinflammatory responses. Central immune mechanisms centered around the blood-brain barrier breach, microglial and astrocytic activation, and propagation of inflammatory signaling pathways leads to neuronal injury, neurotransmitter dysregulation, and functional impairment of brain regions, ultimately manifesting in the clinical symptoms of MDD.

Blood-brain barrier (BBB) integrity

The blood-brain barrier (BBB) is a highly selective, semi-permeable barrier that separates the peripheral circulatory system from the brain and the central nervous system (CNS). It restricts the entry of non-specific immune cells and harmful substances into the brain, protecting the nervous system from external threats. However, when the organism is attacked by inflammation, the permeability and integrity of the BBB is compromised [119], allowing inflammatory factors to enter, exacerbating the neuroinflammatory response and participating in the onset of various neurological diseases including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease and MDD [6, 120–122].

In patients with MDD, the HPA axis got activated, leading to release of glucocorticoids [123]. Glucocorticoids bind to glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) located in the prefrontal cortex and limbic system [124], degrading tight junction proteins [125], enabling the passage of immune cells and inflammation mediators through the BBB, which affect brain function and cause depressive symptoms.

Moreover, under chronic stress, altered neurotrophic factor expression dysregulates tight junction proteins like Cldn5, compromising BBB structural integrity [126, 127]. Inflammatory stimuli like LPS also activate brain endothelial caspase-4/11-GSDMD signaling, leading to inflammatory BBB damage [128].

Studies in chronic restraint stress (CRS) and CSDS mouse models have have demonstrated BBB disruption as a key factor contributing to depressive-like behaviors [129–131]. The excessive release of peripheral pro-inflammatory factors directly acts on endothelial cells, leading to cytoskeletal remodeling and a decrease in the stability of tight junctions, resulting in the increased of BBB leakage [8, 132]. Under chronic stress, the neurotrophic factor GDNF alters the expression of the blood-brain barrier tight junction-associated protein Cldn5. The inflammatory environment impairs BBB structural integrity, promoting BBB hyperpermeability [133]. Additionally, under lipopolysaccharide (LPS) stimulation, the caspase-4/11-GSDMD signaling pathway in brain endothelium is activated, leading to inflammatory BBB damage [128].

Leakage of the BBB allows cytokines and chemokines to enter the brain [134] and interact with various receptors. They directly damage neurons and exacerbate depressive symptoms by decreasing serotonin, dopamine, and norepinephrine levels [135, 136]. Inflammatory mediators entering the brain through the damaged BBB also reduce synaptic plasticity in neurons and impede neurogenesis, affecting mood regulation [137]. Moreover, cytokines and chemokines further activate microglia and astrocytes, creating a feedback loop. Overactivation of microglia releases cytokines such as IL-1β, causing oxidative stress, apoptosis and impairment of neuronal function, all of which are crucial pathological bases for MDD [138]. The entry of IL-1β and TNF-α into the brain via the BBB, induces the production of CXCL1 and Ccl2 from astrocytes, which attracts immune cells to infiltrate brain tissue and damage neurons [139]. Immune cells also enter the brain by upregulating adhesion molecules and integrins, adhering to the vessel wall [140]. T cells and macrophages, enter the brain parenchyma, via the BBB, causing or exacerbating neurological damage and depressive symptoms.

Cytokine and neurotrophic factors

Within the central nervous system, cytokines contribute to neuroinflammation and disruption of neuronal functions underlying mood regulation in MDD [141, 142]. The balance between pro-inflammatory and anti-inflammatory cytokines plays crucial role in the pathogenesis of MDD. Once this balance is disrupted, a vicious cycle emerges wherein an enhanced inflammatory response further triggers depressive symptoms. These symptoms, in turn, may exacerbate the inflammatory response, creating a complex and prolonged pathological process [140].

Pro-inflammatory cytokine TNF-α directly acts on neurons in the brain, inducing oxidative stress and neurotoxicity, activating astrocytes, caus hippocampal atrophy [143–145]. Inhibition of the TNF-α/TNFR1/NF-κB signaling pathway reduces microglial overactivation and neuroinflammation, preventing the worsening of depressive symptoms [146]. Additionally, TNF-α also enhance neuronal excitability by modulating glutamate receptor function and promoting the transcription of Nav1.3 and Nav1.8 [147]. Administration of TNF-α inhibitors infliximab, reduces cortical neuronal activity and ameliorates depressive-like behavior in adults with bipolar depression reporting physical and/or sexual abuse [20, 148].

Clinical studies have shown patients with MDD experience elevated IL-1β concentrations in cerebrospinal fluid and increased hippocampal inflammation [149]. Unlike TNF-α, IL-1β inhibits neuronal excitability by modulating glutamate receptors and decreasing ionic fluxes through voltage-gated sodium channel(Na_v), voltage-gated calcium channel(Ca_v), and voltage-gated potassium channel(K_v) channels [150], leading to depressive-like responses.

IL-6 inhibits excitatory neurotransmission and basal neural activity by promoting the upregulation of the adenosine A1 receptor and modulation of the Ca_v channel [151, 152]. In the cerebrospinal fluid, IL-6 activates the MAPK and IDO pathways, reducing monoamine availability and directly affecting synaptic neurotransmission. It also indirectly affects intracellular pathways through its G-protein-coupled receptor, negatively regulating neurotransmitter release and impacting neuronal activity and plasticity [153].

IFNγ exhibits presynaptic actions that increase the release of the inhibitory neurotransmitter GABA via nitric oxide [154], leading to learning and memory impairments and social behavioral deficits [155]. Blockade of the IFNγ receptor or specific deletion of the IFN-I receptor in microglial cells (IFNAR) reduces synaptic loss, reactive microglial cell proliferation, and learning deficits [9].

Interleukin-4 (IL-4), Interleukin-8 (IL-8), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) play protective roles in the development of MDD [156]. IL-4 regulating hippocampal neurogenesis and resilience to MDD through Arg1 + microglia [157]. Defects in IL-4Rα cause reduced neuronal inhibitory synaptic function and vesicles, increase cortical excitability [158], alleviating depressive symptoms, anxiety, and sleep disturbances [159]. In patients with MDD, IL-10 levels are reduced [160]. Exogenous IL-10 restores the density of dendritic spines in microglia in the hippocampus and alleviate depressive symptoms [161, 162]. Higher levels of IL-8 attenuate depressive responds caused by endotoxin response [163–166]. Lack of these anti-inflammatory cytokines may exacerbate neuroinflammation and mood dysregulation.

Neurotrophic factors are essential for the survival, maintenance, and regeneration of specific neuronal populations in the mature brain, and they significantly contribute to the development of MDD. Brain-derived neurotrophic factor (BDNF) levels are decreased in patients with MDD [167], particularly in the hippocampus [168]. This reduction leads to diminished synaptic plasticity, atrophy of dopaminergic neurons, and atrophy of the hippocampal and prefrontal cortex, primarily affecting brain homeostasis [169]. In vitro studies indicate that the BDNF-TrkB pathway is crucial for forming functional neural networks; blocking TrkB receptors impairs calcium activity, alters synaptic structure, and disrupts mitochondrial function, thus affecting neural network development [170]. In mouse model, knockdown of astrocytic glutamate transporters GLAST/GLT-1 with siRNA in the infralimbic cortex induced behavioral abnormalities characteristic of a depressive-like phenotype, accompanied by reduced serotonin release in the dorsal raphe nucleus and decreased BDNF expression [171]. Conversely, increased BDNF levels support neuronal survival and differentiation, improving the structure and function of multiple brain regions and influence MDD progression [172, 173]. Research on ketamine as a novel antidepressant suggests that BDNF release in the medial prefrontal cortex [174] activates the TrkB signaling pathway, promoting neurogenesis [175–177]. Blocking postsynaptic N-methyl-D-aspartate (NMDA) receptors can rapidly enhance BDNF protein translation [178, 179], coordinating CREB/mTOR activation and leading to synaptic potentiation [180].

Glial cell line-derived neurotrophic factor (GDNF) is also vital for neural function and signal transduction, supporting dopaminergic neuron survival in the substantia nigra and exhibiting protective effects [181]. Studies on conditional Gfra1 knockout mice demonstrate that GDNF and its receptor Gfra1 mediate dendritic growth and spine formation in hippocampal neurons via neural cell adhesion molecule signaling [182, 183]. Another study showed that administering exogenous GDNF increases dopamine receptor D1 protein levels, activating the protein kinase A pathway and producing a prolonged antidepressant response [184]. The rhesus monkey model confirmed that GDNF is widely expressed in hippocampal dendrites, associated with neuronal survival, nerve regeneration, and functional recovery [185]. In addition, clinical studies reveal an association between reduced gray matter volume in the basal frontal lobe in patients with MDD and GDNF [186]. Other neurotrophic factors, such as midbrain astrocyte-derived neurotrophic factor (MANF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), also play protective roles in hippocampal neuronal survival and growth, with decreases hindering the alleviation of depressive symptoms [187–190]. Endothelial growth factor (VEGF), in addition to its angiogenic role [191], possesses neurotrophic and neuroprotective potential [192, 193]. It can stimulate the genesis of hippocampal neurons and safeguard neurons associated with stress from damage [194, 195]. Erythropoietin (EPO) can modulate the JAK2/STAT5 signaling pathway, thereby exerting anti-inflammatory effects and preventing neuroinflammation [196].

Central nervous system inflammation

Compromised blood-brain barrier integrity, along with dysregulated cytokine and neurotrophic factor signaling, predisposes the central nervous system to an inflammatory state. Inflammation activates microglia and astrocytes, causes neuronal damage and apoptosis, impairs functional connectivity and significantly alters the structure and function of critical brain regions (including the hippocampus, frontal lobe, amygdala and striatum) [138, 197, 198].

The hippocampus is predominantly associated with learning, memory, and emotional regulation [199]. Hippocampal volume reduction represents a characteristic alteration in MDD. Reduced hippocampal gray matter volume has been closely linked to memory and emotional disturbances in MDD patients. MDD-related neuroinflammation has also been reported to affect cognitive and memory functions by affecting neurogenesis in the dentate gyrus (DG), leading to inattention, impaired working memory, and increased negative cognitive bias [200]. In addition, reduced serotonin levels lead to neuronal degeneration, swelling, and significant neuronal loss in the hippocampal CA1, CA3, and DG regions, further exacerbates the negative emotional state [201]. Effective antidepressant treatment and electroconvulsive therapy (ECT) has been shown to reverse structural changes in the hippocampus, increase hippocampal volume, and improve depressive symptoms [202, 203].

The amygdala, together with the hippocampus, constitutes key components of the cortico-limbic system, which is essential for emotion processing and regulation [204]. In MDD, amygdala dysfunction is characterized by hyper-reactivity, particularly in response to negative stimuli and decreased functional connectivity between the amygdala and other brain region [205]. Notably, inflammation within the central nervous system (CNS) has been shown to reduce functional connectivity between the amygdala and the ventromedial prefrontal cortex (vmPFC), a disruption that correlates with the severity of anxiety symptoms in patients with MDD [206]. Elevated levels of inflammatory biomarkers have also been associated with increased amygdala activation, which is linked to symptoms of anxious arousal [207]. Recent research demonstrates that peripheral inflammation and amygdala-specific neuroinflammation, as indicated by higher diffusion basis spectral imaging-based restricted fraction (DBSI-RF), are independently associated with depressive symptoms [208]. Clinical studies have shown that selective serotonin reuptake inhibitors (SSRIs) effectively reduce amygdala reactivity to negative stimuli [209].

Frontal lobe exhibits significant structural and functional abnormalities in patients with MDD, particularly in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex (DLPFC) [210]. These changes include reduced gray matter volume, cortical thinning, and decreased activity, which are associated with emotional dysregulation, lack of motivation, and cognitive impairments [211]. The ACC shows altered connectivity with the DLPFC and amygdala, acting as a bridge for attention and emotion regulation [212], while the OFC’s dysfunction reduce inhibition of negative stimuli [213]. Post-mortem brain tissue from Brodmann Area 10 exhibits upregulation of inflammatory cytokines, suggesting a link between local inflammation and pathological changes [214]. Antidepressants, ECT, and transcranial magnetic stimulation (TMS) can partially reverse these abnormalities, correlating with depressive symptom improvement.

The striatum contains the putamen, the caudate, and the ventral striatum. Decreased gray matter volume and activity in the ventral striatum are associated with impaired reward processing and suicidal behaviors in patients with MDD [215]. The putamen shows reduced volume in patients with MDD, its increased functional activity has been linked to emotional dyscontrol and heightened feelings of self-hatred [216]. The caudate nucleus, a key component of the brain’s reward system, also shows reduced volume and activity in MDD, correlating with disease severity and disrupted dopaminergic signaling [217]. Research in non-human primates demonstrated peripheral inflammatory induce decreases in striatal dopamine release, which occur in association with reduced effort-based sucrose consumption [218]. In patients with MDD, peripheral inflammation marked by elevated CRP and sICAM-1, is associated with reduced striatal activation during reward processing, particularly in response to intermediate reward magnitudes [219].

An increased density of microglia has been observed in the amygdala and prefrontal lobes of the brains of depressed patients [220]. Microglia differentiate into multiple phenotypes at different stages of CNS development, stress and disease [221], the polarization of the M1/M2 phenotype is associated with the development of MDD [222–224]. M1 type microglia secrete pro-inflammatory cytokines and neurotoxic mediators to exacerbate neuronal damage, while M2 type microglia promote a repairing anti-inflammatory response. Microglial polarization toward M1 phenotype disrupts neurogenesis in the hippocampus [225], inducing functional brain damage [226, 227]and exacerbating depressive symptoms [228]. Activated microglia release monocyte chemotactic protein-1 (MCP-1), which recruits monocytes to the brain. Subsequently, the brain secretes pro-inflammatory cytokines IL-1β and IL-6 [229, 230], disrupting hippocampal neurons and synaptic plasticity, thereby affecting brain function and inducing MDD [231, 232].

In MDD, the important effects of M1/M2 polarization dysregulation focus primarily on neurogenic inhibition. Although some degree of neurogenesis is also present in other psychiatric disorders like schizophrenia, the mechanism is more prominent in MDD. Unlike with MDD, M1/M2 polarization dysregulation in schizophrenia is mainly characterized by significant neuronal connectivity and neural circuitry abnormalities [233].

Microglia also acquire a neurotoxic phenotype through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which produces reactive oxygen species, nitric oxide, proteases, and pro-inflammatory cytokines that accelerate neuronal damage [234]. This significantly affects the DGs and CA3 region of the hippocampus and leads to MDD. Inhibition of neural stem cell proliferation and differentiation in the DGs, a critical region for neurogenesis, affects pattern segregation in learning memory, and disruption of synaptic connectivity of neurons in the CA3 region, with a reduced density of dendritic spines, leads to cognitive dysfunction and emotion dysregulation [235, 236].

MDD and other psychiatric disorders, such as schizophrenia (SCZ), sahres pathological alterations in the brain, but the patterns and characteristics of these changes differ significantly. MDD is primarily associated with emotional dysregulation, neurocognitive impairments (such as attention and memory deficits), and alterations in reward processing, while schizophrenia cases experience both social cognitive deficits (difficulties in identifying emotions, feeling connected to others, inferring people’s thoughts and reacting emotionally to others [237, 238]) and neurocognitive impairments. For instances, hippocampal abnormalities are observed across both disorders, in MDD, the hippocampus shows reduced neurogenesis prominently in the DGs and CA3 [204]. In contrast, SCZ displays more diverse hippocampal abnormalities, including subfield-specific volume reductions (mainly in CA1 and CA2 regions), synaptic alterations, and disrupted connectivity with other brain regions [239]. Moreover, schizophrenia is associated with broader pathological abnormalities, extending beyond the hippocampus to include regions such as the prefrontal cortex, thalamus, posterior cingulate cortex, and medial temporal lobes [240–242]. These distinctions highlight the unique neurobiological profiles of MDD compared to other psychiatric disorders.

In conclusion, the central immune mechanisms in MDD reveal inflammation as a pivotal orchestrator in disease pathophysiology, driving complex interactions between BBB disruption, neuroinflammation, and neuronal dysfunction. BBB compromise allows peripheral inflammatory mediators to enter the brain, activating microglia and disrupting neural homeostasis. The balance of pro- and anti-inflammatory cytokines, along with neurotrophic factors, critically influences neuronal function, synaptic plasticity, and neurogenesis. This inflammatory cascade particularly affects key brain regions including the hippocampus, amygdala, frontal lobe, and striatum, which ultimately leads to the manifestation of characteristic clinical symptoms of MDD.

Therapeutic interventions targeting immune mechanisms

Pharmacological approaches

Regarding the immune mechanisms involved in the onset of MDD, drug strategies targeting the immune system have become a promising field of research. Clinical studies indicate that antidepressant drugs can reduce the levels of peripheral inflammatory factors and peripheral inflammatory responses [243].

A study by Casarotto et al.pointed out that all antidepressant, including tricyclic antidepressants (TCA), SSRI, monoamine oxidase inhibitors (MAOI), and ketamine are able to directly bind to TrkB and denature to increase BDNF signaling, directly linking the effects of antidepressants to neuronal plasticity, which has important implications for reducing neuroinflammation [244].

Non-steroidal anti-inflammatory drugs (NSAIDs) have shown antidepressant effects in several short-term clinical studies [245]. NSAIDs inhibit COX activity and reduce the synthesis of inflammatory mediators such as prostaglandins, thereby reducing chronic inflammation [246]. Celecoxib, a COX-2 selective inhibitor, protects neurons by inhibiting oxidative stress and in this way mediates its antidepressant effects [247].

Antibiotics also have potential antidepressant effects, with a notable decrease in Hamilton Depression Scale scores in patients with MDD who receive adjunctive treatment with minocycline [248]. Minocycline attenuates the effects of neuroinflammation on MDD by decreasing the expression of proinflammatory cytokines and reducing the release of neuroactive kynurenine metabolites [249].

Inhibitors targeting specific cytokines have also garnered attention. Monoclonal antibodies to TNF-α (e.g. infliximab), IL-6 receptor antagonists (e.g. tocilizumab), and antibodies to IL-4α receptors (e.g. dupilumab) have demonstrated direct and indirect ameliorative effects on depressive symptoms [250–253]. Additional clinical studies have noted positive effects on depressive symptoms with IL-12/23 antagonists [254, 255]. These cytokine antagonists inhibit inflammatory signaling by blocking the binding of cytokines to their receptors, reducing inflammation levels throughout the periphery and brain, and contributing to the recovery of neurological function. Furthermore, given IL-10’s anti-inflammatory role in MDD, reducing IDO expression through IL-10-dependent pathways promote the recovery of MDD [256].

Targeting microglia, particularly over the P2X7-NLRP3 axis, is currently a focus of drug development for neurological disorders, P2X7 activation promotes IL-6 release, stimulates free radical production, phospholipase activation, and apoptosis. In the adaptive immune response, P2X7 stimulation is involved in T-cell activation, and ATP-P2X7 signaling reduces the inhibitory activity and viability of regulatory T-cells (Treg cells) and favors T-cell polarization to T-helper cells (TH17 cells), disrupting the balance between the two and leading to MDD [257]. Brain-permeable P2X7 antagonists can reverse stress-induced depressive-like behaviors [258].

Research indicates that the efficacy of antidepressants varies by gender. Males generally respond better to TCAs, whereas females exhibit greater responsiveness to SSRIs [259]. This difference may result from estrogen’s ability to rapidly shorten the onset time of SSRIs by activating GPER receptors [260]. Additionally, estradiol (E2) enhances the mRNA levels of 5-HT2A and upregulates serotonin transporter expression, contributing to an antidepressant effect [261].

Studies also reveal that females are more sensitive to ketamine dosages, resulting in a more pronounced antidepressant response [262]. Estrogen increases BDNF mRNA and protein levels in the hippocampus, cerebral cortex, and spinal cord [263]. Combined with ovarian hormones’ role in facilitating BDNF signaling, BDNF may mediate the heightened sensitivity to ketamine in females. However, a study on Sprague-Dawley rats showed that ketamine was effective in adult males but ineffective in females [264]. The sexual dimorphism in antidepressant drugs and their mechanisms requires further exploration.

Hormones also significantly influence drug efficacy. Progesterone and estradiol are key estrogens that play vital roles in cellular proliferation, synaptic structure and function, and neuroprotection. They modulate neural activity through various receptors and impact neurotransmitter systems [265]. Additionally, gender differences in antidepressant response are linked to variations in CYP enzymes and the hypothalamic-pituitary-adrenal (HPA) axis [266, 267]. The exploration of gender differences provides critical insights into the use of antidepressants, underscoring the importance of considering patient gender in treatment planning.

Non-pharmacological approaches

Diets that modulate the immune response and inflammatory state are gaining attention in the treatment of MDD. Anti-inflammatory diets, such as the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in omega-3 polyunsaturated fatty acids, antioxidants, and multivitamins, can reduce systemic levels of inflammation and indirectly ameliorate depressive symptoms [268, 269]. By modulating the intestinal microbiota, these diet can increase the production of anti-inflammatory short-chain fatty acids [270, 271]. Additionally, certain prebiotics can promote the growth of beneficial bacteria and maintain neurological stability [272].

Physical activity also provides an important non-pharmacological approach in the management of MDD. Exercise has been demonstrated to contribute to immune system maintenance and gut health, reducing the negative impact of inflammation on the brain by enhancing immune cell function, lowering cortisol levels [273], promoting neurotrophic factor production [274], and optimizing gut microbial diversity.

Psychological interventions serve as an important intervention method of MDD. Interpersonal Psychotherapy (IPT) has been shown to have a significant effect on improving social functioning and reducing depressive symptoms and anxiety [275]. And in children and adolescents with MDD, family therapy may be slightly more effective than individual psychotherapy [276]. Cognitive behavioral therapy (CBT), helps alleviate depressive symptoms by altering cognitive interpretations of stressful events, decreasing the stress response, and consequently reducing the release of inflammatory mediators. CBT also increases the expression of nerve growth factors, such as BDNF, and promotes neural repair and neuroplasticity [277, 278]. Moreover, CBT encourages physical activity, which complemented with exercise therapy, lowers inflammation levels and promotes mood recovery [279–282].

Combining pharmacological and non-pharmacological therapies provides a more comprehensive and personalized approach to MDD treatment. This integrative approach targets the immune system while adjusting the individual’s physiological and psychological state. Such approach considers the multidimensional effects of immunity, neurotransmitters, stress response, and lifestyle, potentially improving treatment efficacy, reduce side effects, and promote long-term recovery for patients.These therapeutic interventions are illustrated in Fig. 2.

Fig. 2.

Therapeutic interventions targeting immune mechanisms in MDD

The figure depicts various therapeutic approaches for MDD, including anti-inflammatory diets, exercise, psychological interventions, non-steroidal anti-inflammatory drugs, antibiotics, targeted therapies against cytokines and their receptors, strategies targeting microglia (P2X7-NLRP3 axis), and cell-derived biomimetic nanoparticles

Conclusion and future directions

The complex interplay between peripheral and central immune mechanisms has emerged as a fundamental pathway in the pathogenesis of major depressive disorder. This review has synthesized current evidence demonstrating how peripheral and central immune mechanisms converge to influence MDD pathogenesis. Multiple pathological processes, including BBB dysfunction, neuroinflammation, and cytokine dysregulation, contribute independently and synergistically to the development and progression of depressive symptoms. While these findings have significantly advanced our understanding, several critical challenges remain to be addressed.

The development of targeted immune-modulating therapies, particularly those addressing BBB dysfunction and neuroinflammation, represents an exciting therapeutic frontier. However, the current evidence for neuroinflammation in MDD, while compelling, has notable limitations. Most studies are correlational rather than causal, and animal models may not fully replicate human complexity. Longitudinal studies tracking inflammatory markers alongside clinical progression could better establish causation, and novel techniques like single-cell sequencing may help unravel cell-type specific contributions to neuroinflammation. By focusing on translational research with clinical applications, we can work toward more effective, personalized treatments for MDD based on immune mechanisms.

The current understanding of immune mechanisms in MDD has opened new avenues for therapeutic intervention and biomarker development, and the success of adoptive cell therapy (such as CAR-T cell therapy) in cancer treatment has inspired scientists to apply similar strategies to immune-related diseases, including MDD. However, there is still relatively little research in this area. Future research is still needed for developing more effective, personalized treatment strategies for this devastating disorder.

Author contributions

Jiao WL, Lin JY and Deng YF conceived the manuscript topic and structural design. Jing X, Ji YL and Jiao WL prepared the figures. Jiao WL, Lin JY and Deng YF drafted and finalised the manuscript with critical input and revisions from Yan FX, Liang CY, Wei SJ, and Jing X.

Funding

This work was supported by the National Natural Science Foundation of China (82204655, 82200616), Medical Research Foundation of Guangdong Province (A2022047), and the Traditional Chinese Medicine Bureau of Guangdong Provincial (20231082). The figures were created with Biorender.com.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.