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Why are people with unfortunate childhood more sensitive and more prone to depression? Why does the risk of mental illness increase with the number of relapses? Stress sensitization may be the answer to these questions.
Although acute stress exposure may be beneficial, repeated or prolonged stress can have negative psychological and physical effects
.
Long-term social stress increases inflammation and impairs mental health
.
Altered communication between the brain and immune system is responsible
for a variety of stress-related psychiatric disorders.
Increased levels of inflammation in the peripheral and central nervous systems have been linked to a number of stress-related disorders, including anxiety, depression, and post-traumatic stress disorder (PTSD).
Revealing key pathways within the immune system may elucidate the underlying pathophysiology of stress-related diseases
.
A November 2022 review by Jonathan P Godbout of The Ohio State University Wexner Medical Center published in the journal Nature Immunology focused on the effects of social stress on the immune system, as well as neuroimmune mechanisms
of stress sensitization.
1
Social stress causes changes in the immune system
Clinically, chronic stressors, inflammation, and mood disorders are associatedwith each other.
Chronic stress can lead to changes in the peripheral immune system in both men and women: long-term care stress or lower socioeconomic status promotes anxiety, which is associated with
an increase in pro-inflammatory monocytes in circulation.
In addition, circulating monocytes were significantly increased in individuals with PTSD, anxiety, and depression, and the severity of PTSD and depressive symptoms correlated
with monocyte NF-κB signaling and glucocorticoid resistance.
The latest study found that the risk of PTSD is related
to 5 alleles at human leukocyte antigen (HLA) sites.
Chronic stress also promotes worsening
of inflammation and psychiatric symptoms by affecting microglia.
Clinical data showed that the inflammatory characteristics of microglia in brain regions such as the hippocampus and prefrontal cortex in patients with depression (especially in patients with suicidal depression), anxiety disorders and PTSD were significantly increased
.
PET data showed that increased activation of microglia in the hippocampus and frontal cortex of first responders in the 2001 World Trade Center attack correlated
with the severity of PTSD symptoms.
2
The brain's adaptive response to social stress
Animal model studies have also demonstrated a linkbetween mood disorders such as chronic stress, inflammation, and anxiety.
At present, the established animal stress models include chronic variable stress, single prolonged stress, restraint stress, predator stress, tail shock stress and chronic social frustration (RSD) stress, which can simulate human emotional disorders
such as anxiety and social behavior deficits.
Of all the stress models, RSD has the strongest effect on the immune system
.
RSD has long-term effects on behavior, physiology, and immunity and increases an individual's sensitivity to a second acute stress a few weeks later, which is known as "stress sensitization.
"
Activation of the central system and peripheral immune system caused by RSD is key
to the development of stress sensitization.
Activation of specific neurons, glial cells, and endothelial cells is the primary response
of the central nervous system to social stressors.
RSD-induced sympathetic nervous system (SNS) and HPA axis activation provides key signals
for the regulation of the immune system.
SNS and HPA activate the released catecholamines and glucocorticoids that act on primary and secondary lymphoid tissues (such as bone marrow), promoting the production, maturation, and release of monocytes into the circulation (Figure 1).
These monocytes have pro-inflammatory and primed characteristics, enter the brain and enrich in fear and threat assessment areas, promoting inflammation
.
On the other hand, these inflammatory monocytes are more resistant to the anti-inflammatory effects of glucocorticoids
.
Figure 1.
Social frustration stress activates the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, promoting monocytes released into circulation
simultaneously with the peripheral immune response.
Microglial recruitment of inflammatory monocytes to the brain is a key process mediating RSD-induced anxiety and other disorders, mediated by highly expressed CCL2 on activated microglia
.
Inflammatory monocytes that aggregate into the brain enhance neuroinflammation
through IL-1 signaling.
In addition, IL-1β produced by inflammatory monocytes acts on IL-1R1 in endothelial cells, enhancing signaling
between the peripheral immune system and the brain.
Notably, IL-1R1 of excitatory VGLUT2+ neurons is also thought to mediate RSD-induced neuronal sensitization and behavioral deficits (Figure 2).
Figure 2.
RSD induces neuronal activation and coordinates peripheral and central immune responses that affect behavior and cognition
3
"Allergic" reactions to social stress
Human sensitivity to stress increases over time, so much so that a slight stressor triggers a mental disorder, a state that becomes a stress-sensitized state.
In animals, stress sensitization is a relatively unique pathological process
of RSD.
After 24 days after the end of RSD, its altered physiological indicators (including monocytes aggregation in the brain, bone marrow monocyte genesis, increased cytokine levels in circulation, etc.
) and behavioral indicators (such as anxiety-like behavior, cognitive impairment, etc.
) returned to normal levels
.
However, some of the abnormal changes persist over time, and changes in three key cell types (neurons, microglia, and spleen monocytes) may be the underlying mechanisms of stress sensitization (Figure 3).
Figure 3.
The role of the central and peripheral immune systems in RSD-induced stress sensitization
1.
Stress sensitization of neurons
in RSD-induced stress sensitization and long-term effects on behavior and cognition.
Abnormal neuronal activation in specific brain regions (e.
g.
, fear and threat assessment brain regions) is the brain's initial response to RSD and is a long-term pathological feature
of diseases such as PTSD clinically.
Stress-sensitized mice are socially avoidant and highly dependent on changes
in neuronal activity.
After stress sensitization, neurons increase their responsiveness to threatening stimuli
.
2.
Stress sensitization of microglia
to the long-term effects of injury, aging, and psychological stress.
"Prination" is an immune-sensitive state of microglia that is more responsive to a second immune stimulus
.
After stress sensitization (after RSD 24 days), microglia in specific regions are in the priming state (high expression of Cd14, Tlr4, and Il6) and are highly responsive to LPS stimulation both in vivo and in vitro
.
Some structural, transcriptome, and functional differences in microglia in the prefrontal cortex remained, but the hippocampus and amygdala returned to normal levels
.
The latest research shows that as a complex process, although microglia are in the priming state after stress sensitization, stress sensitization is not entirely dependent on the initiation of microglia, and other functions of microglia may also play a role
in it.
3.
Stress sensitization of spleen monocytes
in stress sensitization and secondary acute stress-induced anxiety relapses.
After RSD, monocytes are released from the bone marrow into the loop and transported to peripheral tissues, including the spleen, resulting in a unique pool
of monocytes in the spleen after RSD.
After social stress stops, the spleen continues to produce inflammatory monocytes
.
The second acute stress causes a large release of spleen monocytes and collects them in the brain, leading to a recurrence
of anxiety disorders.
The release of spleen monocytes is an important component of
stress sensitization.
summary
The body's adaptive mechanisms to stress and the pathological mechanisms of psychiatric illness are highly complex
.
RSD promotes stress sensitization, causing mice to be highly sensitive to weak subthreshold stress, and anxiety recurs weeks after stress stops, in which neurons, microglia, and spleen all play an integral role
.
Understanding these interactions could help elucidate stress sensitization mechanisms and help provide more targeted treatments
for people with mental illness.
【References】
1.
https://doi.
org/10.
1038/s41590-022-01321-z
The images in the article are from references
