About a century ago, Nobel laureate Julius Wagner Jauregg observed that after a malaria vaccine, people's immune systems are activated and may affect mental function.
Psychoneuroimmunology.
However,PsychoneuroimmunologyIt took decades of stumbling around depression and psychosomatic medicine to form the discipline.
The study noted that as the onset and duration of infection in humans changed, the changes in various psychological parameters were similar to those seen in depression. This means that it is extremely important to study the relationship between depression and immunity. Not only that, but there is a growing recognition that individuals with a higher prevalence of autoimmune diseases also have high rates of depression.
By the early 90s of the 20th century, it was discovered that excessive secretion of immunomodulatory signaling molecules (especially pro-inflammatory cytokines) may play a role in the onset and maintenance of depression (Maes et al., 1995).
It has now been shown that interleukin-6 (IL-6), interferon- (IFN-) cytokines, and other cytokines in patients with depression, including, in particular:Tumor necrosis factor（tumor necrosis factor, tnf）The indicator will be elevated. This inflammatory phenotype is also an important factor in drug resistance to depression**. This theory led researchers to study the antidepressant effects of anti-inflammatory compounds, and the results showed that TNF antagonism in particular improved depressive symptoms in patients.
In addition, the use of pro-inflammatory agents such as interferon (IFN-) ** hepatitis C virus, which causes depressive symptoms in a quarter of patients (Udina et al.).2012）。Given the anti-inflammatory effects of many antidepressant drugs (Hashioka et al.).2007), now arguingNeuroimmune mechanismsIt is central to the development of depressive symptoms.
Immune cells cause an inflammatory response in the brain.
In recent years, there has been increasing attention to the cellular mechanisms of immune transmission to the brain in the context of overall brain health.
Initially, it was believedCentral nervous system (CNS).Somewhat detached from the peripheral immune system. However, there is evidence that circulating cytokines can indeed affect the brain and behavior – althoughBlood-brain barrier (BBB).Immune cell migration to the central nervous system is tightly regulated, but peripheral leukocytes can infiltrate cerebrospinal fluid (CSF), meninges, choroid plexus, perivascular space, and ultimately the parenchyma of the brain (Engelhardt et al.).2017）。
Subsequently, specific innate immune sentinel cells—choroid plexus macrophages, perivascular macrophages, mast cells, meningeal macrophages, and microglia (CNS-resident macrophages)—are the first responders to potentially dangerous detection of pathogens or tissue damage and trigger an immune response (Rua & mcg**ern 2018).
Lymphocytes also accumulate around blood vessels after recruitment to the central nervous system in response to changes in chemokine levels and thus fight pathogens (Rua and MCG**ERN, 2018). Although cytokines are present in the central nervous system at normal homeostasis and play a role in synaptic plasticity, increased monocyte transport and/or alterations in the balance of pro-inflammatory cytokines may lead to the progression of neuroinflammatory events (Dantzer 2018).
In addition, recent studies have shown that in fact, the central nervous system is directly connected to the secondary lymphatic nodes in the neck through a lymphatic drainage system that elicits a peripheral immune response (Louveau et al.).2015）。
2.1 Peripheral innate and adaptive immune system activation during stress and depression
The innate immune system is the first line of defense against infections and stressors, and it is innately present from birth.
on depressionPathophysiologyThe most important thing is that the innate immune system convenes immune cells through the production of cytokines, activation of the complement cascade, and subsequent activation of the adaptive immune system through antigen presentation. Researchers have reported elevated levels of circulating immune cells (e.g., monocytes and granulocytes) in patients with major depressive disorder (MDD) (see Medina Rodriguez et al. for a review2018）。
Many studies have also shown that increased concentrations of immune signaling molecules chemokine and adhesion molecules, such as human macrophage chemoattractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (SICAM-1), E-selectin in the serum of patients with depression, and in the serum of patients with depression as prostaglandins in the acute phase protein and pro-inflammatory cytokines (such as IL-6 or pro-inflammatory factors), suggesting that the peripheral immune system is involved in depression (Miller & Raison 2015).
Similarly, in animals exposed to social frustration stress, neutrophils and macrophages increased (Hodes et al.).2014，wohleb et al.2015）。Inhibition of peripheral blood mononuclear cells leads to alterations in the depressive-like effects of chronic exposure to stress (xZheng et al., 2016). In addition, such as IL-6 (Chourbaji et al.2006) and TNF- (Simen et al..)2006).
Mast cells are innate immune cells involved in the regulation of immune responses and homeostasis support, and play a key role in allergies, cancer, HIV, and colitis. In addition, mast cells are found in the brain, and they play a role in neuroinflammation (Dong et al.).2014), anxiety (Nautiyal et al2008) and the formation of neurodevelopmental pathways associated with sexuality (Lenz et al.).2018).
They have also been shown to be involved in depression through processes that rely on tryptophan metabolism (Georgin L**ielle et al.).2016）。However, further research is needed to uncover the underlying mechanisms of the relationship between peripheral innate immune activity and the development of depression.
Adaptive immunity involves the phenomenon of immune memory, in which specific lymphocytes (T cells or B cells) specifically recognize unique determinants (antigens) in order to respond more effectively when encountering pathogens a second and subsequently. As such, it is a highly specific defense mechanism for the body to respond to specific pathogens.
When studies have shown circulatory accessibility in patients with depressionT cells (TH).The role of the adaptive immune system in depression was initially proposed when the number of cells (CD4+), cytotoxic T cells (CD8+), and B cells increased (Maes et al.).1992）。
Recently, it has been reported that Th2 and Th17 cell maturation is impaired in patients with depression (Grosse et al.).2016), a variety of CD4+ T cell repertoire is reduced (Patas et al.).2018), B regulates cytopenia (Ahmetspahic et al.).2018）。Similarly, studies in animal models have shown that glucocorticoid and stress exposure can modulate T cell and B cell responses (Clark et al.).2019，roque et al.2011）。
Considering that some of the cytokines involved in these processes are associated with the development of disease behavior,Disease behavior is an important coping mechanism in the case of infection, and a long-term imbalance of these molecules can explain the development of symptoms such as nausea, loss of appetite, sleep disturbances, fatigue, and anhedonia（dantzer 2018）。In addition,Cytokines are also associated with the bioavailability of monoamines in the central nervous system, especially in marginal regions that are closely associated with depression（dantzer 2018）。
At the mechanistic level, there is growing evidence that the adaptive immune system plays a role in controlling the stress response. Studies of lymphopenic mice lacking a functionally mature adaptive immune system have shown that the transfer of lymphocytes from agonists to stressed naïve animals can improve social behavior, reduce anxiety-like behavior, and increase hippocampal cell proliferation (Brachman et al.).2015）。Not only did lymphocyte adoptive transfer ameliorate the deleterious effects of stress on animals, but these cells also implanted the choroid plexus and meninges of recipient mice exposed to stress (Sche Inert et al., 2016).
In addition, a recent study reported that although CD4+ T cells do not appear to be directly involved in the stress response, CD8+ cytotoxic T cells respond to stress not only by modulating corticosterone and behavioral responses, but may also induce the production of pro-inflammatory cytokines by inducing monocytes and macrophages (Clark et al.).2019）。In addition, it has been suggested that immune memory of autoantigens may contribute to the development of stress replication mechanisms in the process of relying on memory T cells (Lewitus et al.).2009）。
Depending on the nature of the stress injuryand strongdegree, an increase in circulating immunomodulators may trigger neuroinflammation indirectly through the release of cytokines from peripheral capillary endothelial cells of the blood-brain barrier (BBB) (Spranger et al., 2006), or through vagus nerve stimulation in response to peripheral inflammatory mediators (Eskandari et al., 2003).
In fact, cognitive-behavioral** has been shown to effectively modulate levels of pro-inflammatory cytokines (e.g., IL-6 and TNF-) while reducing depressive symptoms, thus suggesting that a reduction in imbalanced pro-inflammatory signaling is associated with better clinical outcomes (del grande da silva et al.).2016）。
2.2. Inflammasomes and depression
There is growing interest in the role of inflammasomes in stress sensitivity and depression (Fleshner et al.).2017）。, as a response to pathogenic microorganisms or so-called sterile stressors (e.g., psychological stress) (Miller & Raison 2015).InflammasomesIt is a protein complex produced in the cells of the bone marrow lineage. Inflammasome aggregation leads to the activation of caspase-1, which in turn cleaves the precursor forms of IL-1 and IL-18, leading to the activation of these pro-inflammatory cytokines (Strowig et al.).2012) and results in inflammatory cell death, a programmed form of cell death distinct from apoptosis.
One of the first forms of defense implemented by specific innate immune cells during infection is the presentation of a groupPattern recognition receptors（pattern recognition receptor，prr）, these receptors are encoded in the germline and are used to recognize molecular patterns of expression of invading pathogens. These may be located on the surface of the membrane, as in the Toll-like receptor (TLR), or inside the cytoplasm, as in:NOD-like receptors (NLRs).（kaufmann et al.2017）。
NLRs are cytosolic receptors that are capable of recognizing non-self molecular and associated cellular damage and are triggered by pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) (Kaufmann et al., 2017). NLRP3 is a subset of NLR and is the most studied inflammasome involved in caspase-1 activation;It is expressed in the central nervous system of microglia and undifferentiated neurons (Fleshner et al.).2017）。
Rodent studies have shown that chronic stress leads to overexpression of NLRP3 in microglia (Pan et al2014，y.zhang et al.2015，zhu et al.2017), selective serotonin reuptake inhibitors (SSRIs) antidepressants can reverse this (Pan et al.).2014）。In addition, in other stress models, modulators targeting specific glia and neurons improved depression-like behavior while modulating the NLPR3 inflammasome (Z.).-q.li et al.2018，yue et al.2017）。
In addition, lipopolysaccharide (LPS) was administered (Jeon et al.).2017) or exposure to chronic non-mild stress (SU et al.).2017) showed a reduction in depression-like behaviors, further reinforcing NLRP3's involvement in this stress-inducing behavior. In humans, overexpression of NLRP3 was observed in peripheral blood cells in patients with MDD without **, along with elevated serum levels of IL-1 and IL-18, which was reversed by antidepressant ** (Alcocer-Gómez et al.).2017）。
Therefore,Inflammasomes may be important regulators of inflammatory responses, although the mechanism of this complex reaction is unknown. However, feedback loops initiated by cytotoxic T cells trigger the LRP3 inflammasome in antigen-presenting cells to promote IL-1 maturation, suggesting that the feedback loops produced by adaptive immune cells help stimulate innate immune cells to enhance innate immunity (Yao et al.).2017）。
2.3.Neuroimmunity, stress, and depression
There is growing evidence that there is a neuroimmune basis for depression (Bekhbat &Neigh 2018). As previously mentioned, microglia are key innate sentinel immune cells that are confined to the central nervous system and monitor the environment with motor protrusions to determine changes in the physiological environment.
In addition to their critical role as response agents of infection and injury, microglia are involved in neuronal events, including synaptic remodeling, at different stages throughout neurodevelopment and adulthood to form neuronal network signals (Norris &Kipnis 2019).
These cells are involved in a dynamic system, the neurovascular unit, which includes cells that surround the blood-brain barrier (BBB) and transmit the interactions between CNS cells and peripherals (Banks 2016). Recent studies have shown that microglia are maintained in the brain through self-renewal and maintain long-term interactions with neurons. In addition, microglia can release inflammatory cytokines to affect neuronal activity and neurotransmitter receptor transport, as well as gene expression.
In addition, neurons regulate microglial function through soluble factors, including chemokines, cytokines, and neurotransmitters (CX3CL1, TGF, CSF1, UDP, ATP, glutamate, GABA, norepinephrine), to promote microglia function and cellular adaptation, direct locomotion and phagocytosis, and initiate and propagate appropriate inflammatory responses (Wohleb 2016).
Mutual communication between microglia and neurons may promote neuroplasticity, neurogenesis, proliferation, pruning, and neurodegeneration throughout the lifespan, and may play a key role in stress and neuroinflammatory responses (Li&Barres 2018).
Glucocorticoid receptors are widely expressed on microglia throughout the brain (Sierra et al., 2008), and the integration of stress-induced signals in the central nervous system is mediated by regulated microglia through neuroinflammatory signaling (Wohleb et al., 2014). In response to stress, microglia undergo dynamic changes in morphology and function in the limbic region of the cortical associated with depressive-like symptoms.
Under stress conditions, neuroendocrine pathways fine-tune central and peripheral immune responses, leading to monocyte transport and initiation, followed by changes in the microglial phenotype, which ultimately leads to neuroinflammation, which in turn leads to the development of multiple stress-related diseases, including depression (Hodes et al.).2015）。
Released upon exposure to microglia activationCytokines have been implicated in the development of aberrant behavioral phenotypes in stress models。Thus, cumulative evidence suggests a clear link between cytokine release and the activity of the HPA axis.
A recent study showed that immunization with Mycobacterium bovis, a bacterium with immunomodulatory and anti-inflammatory properties, can improve anxiety-like behaviors caused by exposure to stress by attenuating pro-inflammatory microglia initiation (Frank et al.).2018）。
Through choroid plexus cells (Kunis et al.).2013) and BBB (Capuron & Miller 2011, Turrin & Rivest 2004), immune challenge can also stimulate the activity of the HPA axis by translocation of immunomodulators. In fact, under physiological conditions, lymphocytes are present in small numbers in the brain parenchyma and are mainly concentrated in the choroid plexus, meningeal space, and cerebrospinal fluid. Curiously, there is evidence that T cells aggregate in these regions in response to signals triggered by the central nervous system, i.e., in the meninges while performing cognitive tasks (Derecki et al.).2010), or, strikingly, in the choroid plexus after stress exposure (Lewitus et al.).2008）。
Notably, the most common type of glial cell in the central nervous system is astrocytes, which play a key role in maintaining brain function and regulating neurotransmission, metabolism, and energy** (qWang et al., 2017). A decrease in astrocyte density and number has also been reported in patients with depression (Rajkowska and Miguelhidalgo, 2007).
Recent human brain imaging studies using transporter protein 18 kDa (TSPO) as a marker for reactive astrocytes and microglia have shown that neuroinflammation is increased in MDD patients, and antidepressants** reduce this inflammation (Richards et al.).2018）。
Summary
Taken together, these findings clearly suggest that depression is a complex psychiatric disorder that is intrinsically linked to stress maladaptation, leading to dysregulation of the HPA axis and immune system. Over the past few years, we have clearly seen that this altered stress and inflammatory response is focused on brain function, disrupting normal neuroimmune homeostasis.
Thus, in the field of immunopsychiatry, the idea that targeting this altered stress-immune axis could lead to new approaches to depression** has generated great enthusiasm (Pape et al.).2019）。Recently, however, a new participant emerged with the gut microbiota, which is also a key regulator of stress and inflammation, so its role in depression is also being studied.
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