2. Possible Triggers of Microglial Inflammatory Activation in Stress-Induced Depression
Tissue damage or infection can induce microglial inflammatory activation by releasing proinflammatory mediators
[44][23]. In contrast, the exact triggers of microglial inflammatory activation under sterile inflammatory conditions such as chronic psychosocial stress are unknown. Chronic psychosocial stress causes cellular and structural changes in the brain, resulting in altered neurocircuitry and depressive behavior
[41,45,46][24][25][26].
In thRe
following sections, we searchers discuss inflammatory factors that trigger the activation of microglial cells in response to psychosocial stress in animal models (
Figure 1). Animal models used in preclinical studies of depression often use stressors to induce depression-like pathology
[47][27]. While some of these models may not accurately reflect the actual pathophysiology of human depression, they consistently exhibit features such as hyperactive HPA axis, impaired neuroplasticity and neurogenesis, and altered neurotransmitters that can be related to human depression
[28,48,49,50][28][29][30][31]. These models have greatly contributed to
ourthe understanding of depression, particularly in revealing the role of neuroinflammation in its pathophysiology
[47][27].
Figure 1. Triggers and role of microglial inflammatory activation in the pathogenesis of depression. Chronic psychosocial stress can increase hyperactivity of the hypothalamic-pituitary-adrenal axis, activation of peripheral immune cells, and release of damage-associated molecular patterns (DAMPs). Stress can also disturb communication between microglia and neurons that regulate microglial immune responses. Inflammatory signaling in microglia increases the expression of proinflammatory cytokines and the generation of reactive oxygen species (ROS). Inflammatory microglia also show decreased neurotrophic signaling, which hampers the release of brain-derived neurotrophic factor (BDNF) from microglia. These changes culminate in neuronal damage, including decreased neurogenesis, dendritic spine density, and impaired synaptic plasticity, leading to depression. ↓, decrease; ↑, increase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; C1q, complement component 1q; TNF, tumor necrosis factor; MeCP2, methyl-CpG binding protein 2; CREB, cAMP response element binding protein; ERK, extracellular signal-regulated kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma, NLRP3, nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing protein 3.
2.1. Hyperactivity of HPA Axis
Neuroendocrine responses to psychosocial stressors are an important compensatory mechanism
[51][32]. The classical “fight-or-flight ” response leads to hyperactivity of the HPA axis, increasing circulating glucocorticoids and catecholamines that return to baseline levels after the threat wanes
[52][33]. In chronic psychosocial stress, however, persistently increased HPA activity exerts deleterious effects on the brain
[53][34]. Chronic stress can lead to maladaptive changes in the HPA axis, which can contribute to the development of depression
[52][33]. In vivo models have shown that the upregulation of HPA activity varies according to the type of stressor, which also reflects variable levels of glucocorticoids in a subset of patients with MDD
[53][34].
The brain responds to stress by identifying potential threats and triggering corresponding physiological and behavioral reactions that can either be beneficial or harmful
[51][32]. The brain is the main target of glucocorticoid actions, which are elevated after exposure to stressful stimuli
[51][32]. All major cell types of the brain, including neurons, astrocytes, and microglia, express glucocorticoid receptors
[54,55][35][36]. These receptors are expressed in distant limbic–midbrain and cortical brain regions, including the hippocampus, amygdala, and prefrontal anterior cingulate cortex, suggesting the role of glucocorticoids in stress-related mood disorders
[56][37]. Importantly, distinct hippocampus regions show varied sensitivities to glucocorticoid activity
[50][31]. The hippocampus plays diverse roles in memory and behavior due to functional segregation along its longitudinal axis. The dorsal hippocampus primarily contributes to spatial learning and memory, whereas the ventral hippocampus mainly regulates anxiety, which is influenced by stress. Due to its direct connection to the hypothalamus, the ventral hippocampus is more prone to the deleterious effects of glucocorticoids compared to the dorsal hippocampus
[57][38].
Given the impact of the HPA axis on stress neurocircuitry, the increased HPA axis may drive the phenotypic transition of microglia in chronic stress-induced depression
[49][30]. Indeed, recent literature has reported that increased HPA axis activity drives the primed state of microglia and induces the inflammatory phenotype in stress-sensitive brain regions
[49,58,59][30][39][40]. Increased serum glucocorticoid levels were found in both preclinical and clinical studies of MDD
[60][41]. Glucocorticoids also increased NLRP3 inflammasome signaling in the hippocampal region of mice subjected to chronic restraint stress
[58][39]. Increased levels of high-mobility group box 1 (HMGB1) in limbic regions of the rat brain were reported in a model of inescapable tail shock, where subsequent administration of an antagonist blocked glucocorticoid signaling and attenuated the increase of HMGB1 levels
[59][40]. In addition, increased inflammatory signaling in microglia was observed in a mouse model of corticosterone-induced depression
[61,62][42][43]. Increased levels of proinflammatory cytokines in microglia were accompanied by depressive-like behavior in mice injected with corticosterone
[63][44].
2.2. Peripheral Signals: Brain-Immune Axis
The brain is a distinct structure separated from the rest of the body by the blood-brain barrier (BBB). BBB acts as a selective barrier, regulating peripheral access to the brain parenchyma. The loss of BBB integrity has been documented in MDD pathophysiology, but the role of peripheral signals in microglial activation in vivo is debatable
[64][45]. Immune dysfunction has been documented in patients with MDD as well as in preclinical models of depression
[65,66,67][46][47][48]. Peripheral immune cells are the major sources of circulating proinflammatory cytokines that can induce inflammatory activation of microglia
[68][49]. In addition, peripheral immune cells infiltrate the brain parenchyma in various animal models of depression
[69][50]. Whether these peripheral immune cells trigger microglial activation in depression is unclear.
In a CSDS model, susceptible mice exhibited decreased expression of claudin-5, a tight junction protein in the BBB, which allows peripheral immune cells and proinflammatory cytokines to enter the brain
[48][29]. Moreover, transcriptomic analysis of endothelial cells from susceptible mice revealed increased expression of genes associated with the proinflammatory tumor necrosis factor-α (TNF-α) and the NF-κB pathway
[48][29]. The study also found decreased claudin-5 expression in post-mortem samples of patients with MDD
[48][29]. Thus, a compromised BBB can allow proinflammatory signals from the periphery to act on microglia in a depressed brain.
Increased trafficking of monocytes to the perivascular space and parenchyma was also observed in the repeated social defeat model
[69][50]. Using chimeric mice expressing the green fluorescent protein in lysozyme M (LysM)-positive myeloid cells, the study found an increased infiltration of monocytes in various brain regions of defeated mice. Interestingly, significant increases in IL-1β, chemokine (C-C motif) ligand 2 (CCL2), and microglial activation were also found in brain regions in which peripheral macrophages infiltrated
[69][50]. Finally, the study found that crosstalk between chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) recruits macrophages to the brain parenchyma under stressful conditions
[69][50].
Contrary to these findings, another group found that peripheral immune cells do not play a role in microglial inflammatory activation in acute and chronic social defeat stress models
[70][51]. Here, chronic social defeat increased phagocytic microglial cells in the brain without recruiting peripheral immune signals, indicating that microglia are solely responsible for generating inflammation in the brain during chronic stress. Moreover, peripheral signals can attenuate pathways involved in monoamine synthesis. A recent study showed that lipopolysaccharide-binding protein (LBP) expression increased both peripherally and centrally in mice following exposure to stressful stimuli
[71][52]. LBP expression also increased in microglial cells and inhibited enzymes involved in synthesizing monoamine neurotransmitters. These findings suggest a bidirectional communication between neuroendocrine stimuli and the immune system in the pathology of depression.
2.3. Neuronal Signals Shape Microglial Responses
Microglia and neurons work together by secreting diverse molecules to regulate brain homeostasis. Particularly, neuronal-derived soluble factors, including colony-stimulating factor 1 (CSF1), CX3CL1, and transforming growth factor-β (TGFβ), play crucial roles in regulating microglial immune functions
[72,73][53][54]. Dysregulation of neuronal activity and neuronal atrophy following stress alters neuronal-derived factors that maintain microglial activity, leading to increased inflammatory signaling in microglial cells
[74][55]. Mice exposed to the chronic unpredictable stress model displayed increased expression of CSF1 in the PFC as well as CSF1 receptor (CSF1R) in microglial cells in the same region
[72][53]. Augmented CSF1 signaling in microglia increased phagocytosis of neuronal elements, which reduced dendritic spine density. Interestingly, the knockdown of neuronal CSF1 decreased microglial phagocytosis and attenuated behavioral deficits in stressed mice. Impaired CX3CL1-CX3CR1 signaling between neurons and microglia has also been shown in an animal model of chronic stress, causing inflammatory activation of microglial cells
[75][56]. Microglial deletion of CX3CR1 prevented mice from developing depression-like behavior after stress exposure. Ultimately, CX3CR1 deficiency attenuated chronic stress-induced proinflammatory gene expression in microglia and prevented neuronal dysfunction
[76][57].
2.4. Role of Damage-Associated Molecular Patterns (DAMPs)
Studies have reported that damage-associated molecular patterns (DAMPs), including heat shock proteins, HMGB1, and S100 proteins, can initiate sterile neuroinflammatory processes in animal models of chronic psychosocial stress
[77][58]. Microglia can recognize these DAMPs and transmit signals to intracellular NLRP3 inflammasomes through TLRs and RAGE
[29,66][47][59]. These immune receptors have been shown to promote microglial inflammatory signaling in an animal model of chronic stress and depression.
In addition to increased mRNA levels of HMGB1 in hippocampal microglia, higher expression of RAGE and activation of NLRP3 inflammasomes were found in the CUMS model of depression
[29][59]. The increased HMGB1-RAGE signaling in hippocampal microglia coincided with depressive-like behavior in mice exposed to chronic unpredictable stress. Increased expression of S100a8 and S100a9 was also found in the PFC of susceptible mice subjected to repeated social defeat stress
[66][47]. Microglia-specific reduction of TLR2/4 expression by using a viral strategy, however, prevented mice from developing depressive-like behavior after repeated social defeat stress
[66][47]. Increased HMGB1 expression was also observed in the hippocampal region in rat brains following inescapable tail shock. Increased HMGB1 expression positively correlated with heightened NLRP3 inflammasome signaling
[78][60].
Chronic stress can trigger not only previously well-recognized DAMPs but also extracellular nucleosomes and histones. Increased histones and nucleosomes were found in the cerebrospinal fluid of the CUMS mice, which positively correlated with IL-1β levels in PFC
[79][61]. Higher levels of nucleosomes promoted microglial inflammatory signaling in a C-type lectin receptor 2D (Clec2d)-dependent manner, increasing oxidative stress and IL-1β secretion
[79][61]. Knockdown of Clec2d in PFC reduced microglial inflammatory activation and depressive-like behavior in CUMS mice.
3. Microglia as a Potential Therapeutic Target for Treatment of Stress-Induced Depression
Inflammatory activation of microglia in various limbic brain regions is a hallmark of chronic psychosocial stress not only in rodents but also in humans
[91,92][62][63]. Patients with MDD exhibit increased proinflammatory cytokines in cerebrospinal fluid, decreased neurogenesis, and impaired synaptic plasticity
[91,92][62][63]. Inflammatory activation of microglia is strongly linked to neuronal deficits in MDD pathology; therefore, microglial inflammation is a potential therapeutic target for treating depression. Various strategies have been used effectively in in vivo models of depression to mitigate inflammatory activation of microglia (
Table 1).
Table 1.
Targeting microglial inflammatory activation in animal models of depression.
Putative Microglial Targets |
Targeting Strategies |
Animal Models |
Brain Regions |
Outcomes |
References |
↓ NLRP3 signaling |
MCC950 |
CUMS (Mice) |
PFC |
↓ Depressive-like behavior ↓ Neuroinflammatory markers ↓ IL-1β |
[93] | [64] |
↓ NLRP3 signaling |
Astragalin |
CUMS (Mice) |
Hippocampus |
↓ Depressive-like behavior ↓ Neuroinflammatory markers ↓ IL-1β |
[94] | [65] |
↓ p38 MAPK signaling ↓ NF-κB signaling ↓ HMGB1/RAGE/TLR4 signaling |
Roflupram |
CUMS (Mice) |
Hippocampus PFC |
↓ depressive-like behavior ↓ proinflammatory cytokines |
[95] | [66] |
↑ BDNF signaling |
Viral-mediated overexpression of IL-4 |
CMS (Mice) |
Hippocampus |
↑ Neurogenesis ↓ Depressive-like behavior ↓ Proinflammatory cytokines ↑ Arg-1 positive microglia |
[96] | [67] |
↑ BDNF by increasing Nrf2 signaling ↓ MeCP2 expression |
Sulforaphane |
CSDS (Mice) |
PFC |
↑ Resilience to stress ↑ Synaptic plasticity ↓ Proinflammatory cytokines |
[97] | [68] |
↑ ERK-NRBP1-CREB signaling ↑ microglial BDNF |
(R)-Ketamine |
CSDS (Mice) |
PFC |
↑ Dendritic spine density long-lasting antidepressant action |
[98] | [69] |
↓ NLRP3 signaling ↑ Autophagy |
Ketamine |
CRS (rats) |
PFC Hippocampus |
↑ Synaptic plasticity ↓ Depressive-like behavior |
[99] | [70] |
↓ CSF1 receptor expression ↓ CD11b ↓ (CR3)-C3 phagocytic pathway |
Diazepam |
CUS (Mice) |
PFC |
↑ Dendritic spine density long-lasting antidepressant action |
[100] | [71] |
↓ ERK 1/2 signaling ↓ Phagocytic microglia |
Minocycline |
CMS (Mice) |
Hippocampus |
↑ Neurogenesis ↓ Depressive-like behavior |
[101] | [72] |
↓ HMGB1 release |
CUMS (Mice) |
↑ Cognitive performance ↓ Depressive-like behavior |
[102] | [73] |
↓ Phagocytic microglia |
CSDS (Mice) |
↓ Proinflammatory cytokines ↓ Synaptic loss ↓ Behavioral despair |
[103] | [74] |
↓ Phagocytic and inflammatory microglia |
CUMS (Mice) |
PFC Hippocampus |
↑ Kynurenic acid ↓ Behavioral despair |
[104] | [75] |
↑ LXR- β signaling ↓ NF-κB signaling ↓ NLRP3 signaling ↓ IL-1β ↓ Phagocytic microglia |
TO90137 |
CUMS Corticosterone-induced depression |
Basolateral amygdala |
↓ Neuroinflammation ↓ Depressive-like behavior |
[105] | [76] |
↑ LXR- β signaling ↓ NF-κB signaling |
GW3965 |
CUMS (Mice) |
Hippocampus |
↓ Inflammatory markers ↓ Synaptic impairment |
[106] | [77] |
↑ PPAR-γ signaling ↑ Neuroprotective microglia |
Asperosaponin VI |
CMS (Mice) |
Hippocampus |
↑ Microglial-neuronal interactions ↓ Synaptic deficits |
[107] | [78] |
Not discussed |
murine recombinant IL-10 |
Learned helplessness (mice) |
Hippocampus |
↑ Dendritic spine density ↑ Cognitive performance |
[108] | [79] |
Not discussed |
Dimethyl fumarate |
CUMS (mice) |
Hippocampus |
↓ Neuroinflammatory markers ↓ Cognitive impairment |
[109] | [80] |