English Session 2

Journal Reading of :

STRESS, NEUROIMMUNE AND

NEUROENDOCRINE RESPONSE

Submitted by:
dr. Tjoeng Steven
S571702001

Supervisor:
Prof. Dr. dr. M.Fanani, SpKJ (K)
dr. IGB. Indro Nugroho, Sp.KJ

PSYCHIATRIST RESIDENCY FACULTY OF MEDICINE

SEBELAS MARET UNIVERSITY/RSUD Dr. MOEWARDI
SURAKARTA
2019

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 VALIDATION

Presentation : English Session 2 , Journal Reading of “STRESS, NEUROIMMUNE

AND NEUROENDOCRINE RESPONSE”
Nama : Tjoeng Steven, dr.

PSYCHIATRIST RESIDENCY I FACULTY OF MEDICINE

SEBELAS MARET UNIVERSITY / RSUD Dr. MOEWARDI

SURAKARTA

It has been approved on :

_________________________________ 2019

Supervisor

Prof. Dr. dr. M.Fanani, SpKJ (K) dr. IGB. Indro Nugroho, Sp.KJ

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 PAGE OF APPROVAL

English Session Presentation

STRESS, NEUROIMMUNE AND NEUROENDOCRINE RESPONSE

Has been approved to be presented on

Date………..…………… 2019

Supervisor Tanda Tangan

1. …………………………………… …………………………

2. …………………………………………. ………………

3. …………………………………………. ………………

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 STRESS, NEUROIMMUNE AND NEUROENDOCRINE RESPONSE

Margarita M. Maramis
Consultant psychiatrist in Biological Psychiatry and Neuroscience Division, lecturer at
Psychiatric Department Dr. Soetomo General Teaching Hospital – Universitas Airlangga,
Surabaya

Abstract
Stress has profound effects on the structure and function of the brain at the cellular and
subcellular levels. The response of the brain to stressors is a complex process involving multiple
interacting system such as neurotransmitter, neuroendocrine, neuroimmune, autonomic nervous
system, apoptotic cascade, intracellular process, etc.
The major areas of the brain most affected by stress are the hippocampus, prefrontal cortex, and
amygdala, probably because these areas contain abundant glucocorticoid receptors. Additionally,
neurons in these regions are known to be highly plastic, both functionally and structurally, in
response to repetitive activation. Neurons in the hippocampus, prefrontal cortex, and amygdala
are highly sensitive to stressful stimuli, resulting in significant changes in their structure and
function even at the molecular level.
Long has been known that stress response of neuroendocrine system is through HPA axis
(Hypothalamus-pituitary axis). This will lead to release cortisol and its feedback system. In the
neuroimmune system, there is also activation of cytokines, which is in turn influence
neurotransmitter system, neuroendocrine system and autonomic nervous system as well.
Therefore, recovery of stress-induced changes in neural architecture after stress is not a
“reversal” but a form of neuroplasticity adaptation. Intervention such as psychopharmacology
and psychotherapy is given to stimulate this neuroplasticity adaptation.

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Background
Through life, in self and life threatening condition, human will apply coping mechanism.
The most primitive coping mechanism are fight, or flight, or freeze.
Stress defined as internal condition caused by physical needs towards illness, exercise,
extreme temperature or by social and environment condition, which evaluate as harm,
uncontrollable or beyond the coping. Physical, environment, and social incident that cause stress
called as stressor. Stress happens while people perceive that they cannot resolve the needs and
threats towards their welfare (Lazarus RS, 1966).
Cox (1975) defined stress as involving external stimulus, physical response to the
stimulus and psychological process that may mediate stimulus and response. Psychological
process may include differences between individual and his perception to need for protection and
self‟s ability to encounter.
Based on medical dictionary, stress is physical, mental, and emotional factors, which
cause tense on body or mental. Stress can be from either external (environment, psychological or
social situation) or internal (illness or medical procedure).
External and internal stimulus on human will activate hypothalamus-pituitary axis (HPA
axis). Human is prefer to prolong period of the same system activity enhancement, that may help
coping acutely. Prolong of the enhancement can be caused by anxiety; constant exposure of poor
environment; interpersonal conflict and lifestyle and habit modification related to chronic
stressor illness. Selye emphasized adrenocortical system as notable response in result to stress
stimulus. Increasing of HPA axis activity frequently happens in recent event observation or
change of the system‟s stability.

Physiological response to stressor

Hans Selye (1907 – 1982) may describe physiological response to stressor as General
Adaptation Syndrome (GAS) model. First stage is alarm reaction, initial response of the body
towards stressor/stimulus. This stage consists of shock stage and counter shock stage, where
decline comes first in shock stage, then followed by enhancement at counter shock stage.
Whether stressor continues, then the body enters resistance stage reaction or adaptation. During
this stage, body shows resistance to several stressor exposure, then over time enters exhaustion
stage. In this stage, animal experiences the same symptoms as alarm reaction and loss of

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adaptability of previous stage. When long exhaustion stage continues, the animals may die
(Taylor et al., 2012). (Figure 1).

Figure 1. Scheme of three stage of General Adaptation Syndrome (GAS) resistance change by
Hans Selye (1946). Resistance towards stressor decreases in shock stage of alarm reaction and
increases during counter shock stage, then reach the peak during resistance stage. Further, in
exhaustion stage, decreases below normal, lastly the animals may die (Taylor et al., 2012).

In a chronic stress state, for example in depression disorder, hyperactivity of

hypothalamic-pituitary-adrenal axis occurs. It causes decline of negative feedback from
glucocorticoid, which reduces signal of HPA axis, leads to enhancement of corticotrophin-
releasing hormone (CRH) secretion from paraventricular nucleus (PVN) in hypothalamus and
extra-hypothalamic nerves. Releasing of CRH involves TNF-α, IL-1, and IL-6 to stimulate
ACTH hormone from anterior pituitary (Gadek-Michalska et al., 2013). Physiologically,
glucocorticoid leads negative feedback to immune cell to suppress excessive synthesis and
release of cytokines. The negative feedback happens in different stages and areas, including
hippocampus (Guidotti et al., 2013).
Moreover, in a chronic stress state, inhibition of cytosolic negative feedback of
glucocorticoid receptor (GR) level system in PFC and hippocampus occurs, that leads to
excessive of cytokine IL-6 synthesis (Silverman et al., 2005; Arnsten, 2009). Further, IL-16 may

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stimulate HPA axis (Raber et al., 1997), so that in a negative glucocorticoid negative feedback
disorder, will increase IL-6 and glucocorticoid level because of the stimulation. It becomes a
vicious circle that leads to inflammation, delivers other proteins modulation.

Relationship between HPA axis system and immunity system

Among several system in human body is interconnected and works together to maintain
survival of cell metabolism stability. Immunity system through early innate pro-inflammatory
cytokines (TNF-α, IL-1, and IL-6) and interferon, then late acquired T-cell cytokines (IL-2, INF-
γ) stimulate releasing of glucocorticoid by negative feedback of immune system to inhibit pro-
inflammatory cytokines inhibition (dashed red line). Glucocorticoid plays an important role to
immune system afterwards by changing type of the immune response, cellular immunity
(Th1/inflammatory) to humoral immunity (Th2/anti-inflammatory). Therefore, glucocorticoid
protects organism from damage due to overactive response of inflammatory immune system
(Silverman et al., 2005). (Figure 2)

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 Figure 2. Bidirectional communication between immune system and hypothalamus-pituitary-
adrenal (HPA axis) in human brain. ACTH=adrenocorticotropic hormone; AVP=arginine
vasopressin; CRH=corticotrophin releasing factor; hipp=hippocampus; IFN=interferon;
IL=interleukin; ME=median eminence; PVN=paraventricular nucleus of the hypothalamus;
TNF=tumor necrosis factor (Silverman et al., 2005).

Stress effect in stress protein Heat Shock Protein 70 (Hsp 70)

Heat Shock Protein (HSPs), also called as stress protein, expressed by intrinsic and
extrinsic stressor (Taylor et al., 2007). HSP70 includes a large group of proteins, which prevents
damage in plant, bacteria, fungal, and mammal cell. Extrinsic stressor from the environment,
such as higher temperature, viral infection, ischemic, anoxia, oxidative stress (Basson, 2006),
intrinsic stressor such as physiological change, inflammation, metabolic stress and illness
(Pedersen et al., 2005; Taylor et al., 2007; Haak and Kregel, 2008), and psychological stressor
(Williams and Hunter-Lavin, 2007) may induct HSP.

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 HSP responds to normal state while physical exercise. Stress state triggers defensive
mechanism from cell, which has the role as emergency system to counter stressor, results in
misfolded proteins accumulation (Basson, 2006).
Since 10 years ago, it has been hypothesized that small vesicles, called as exosomes,
actively makes cell to release HSP. Exosomes are secreted by several hematopoietic cell such as
T and B-lymphocytes, dendritic cells, macrophages, and platelets (Lancaster and Febbraio,
2007), also several tumor cell lines, peripheral blood mononuclear cells (PBMC) (Williams and
Hunter-Lavin, 2007). It is possible that releasing of HSP due to stress related exosome is specific
to this cell type (Lancaster and Febbraio, 2007).
HSP has been classified based on molecular weight in kilo Dalton (kDa) and determined
by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Moreover, it has
divided to 5 families: HSP100, HSP90, HSP70, HSP60, and small HSP (sHSP), including αB-
crystalline with molecular weight 12 – 43 kDa (Basson, 2006; Richter-Landsberg, 2007).
Production of HSP is important as the response to heat reaction and other stress. In unstressed
cell, this protein has important function for various protein metabolism aspects (Basson, 2006).
HSP has many roles in physiological process such as cell cycle control, cell proliferation,
cell growth, organization of cell cytoarchitecture, cell death and preservation regulation, cell
aging, directly lead to cell apoptosis and necrosis. HSP role in synthesis, folding, transport, and
translocation of the proteins is as main chaperon molecule in the cell (Basson, 2006; De Los Rios
et al., 2006; Richter-Landsberg, 2007; Haak and Kregel, 2008).
HSP accumulates and help misfolded and aggregated proteins, so that may be more
tolerance towards further stress due to stress state. HSP works along with ubiquitin proteasome
system during protein quality control process. In the neurons and glia, HSP expresses and
responds towards various stressor specifically (Basson, 2006; Richter-Landsberg, 2007), protects
neurons (Guzhova et al., 2001; Yenari, 2002) and has an anti-apoptotic activity (Franklin et al.,
2005).
Mechanism of HSP in responding stress state: (1) various physiological signal, including
hyperthermia, hypoxia, lack of energy, and ROS (Reactive Oxygen Species) may activate Heat
Shock transcription Factors (HSF). Activated HSF enters nucleus and binds to Heat Shock
Elements (HSE) in the promotor region of HSP70 gen. Then, HSP70mRNA is transcribed and
leaves the nucleus to the cytosol, where recent HSP70 is synthesized. (2) Due to stress response,

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HSP70 binds to misfolded protein in the cytoplasm and helps unfolding and refolding to the
original form. HSP70 may also binds to denatured peptide through stress or new peptide chain
results (3) refolding protein into the original form or (4) prevents protein aggregation. (5) HSP70
may binds to denatured protein due to stress or new peptide chain, this complex is transported to
various cell organelle, including mitochondria and endoplasmic reticulum (Haak and Gregel,
2008). See figure below:

Figure 3. Scheme of cell response to classic stress including HSP72kDa (HSP70) activation and
several intracellular roles (Asea et al., 2000; Asea et al., 2002).

Overexpression of HSP70 in the nerves and glia leads to neuron protection which also
has role in death and preservation cell regulation, related to neurodegenerative disorder and
inflammation of nervous system (Basson, 2006; Richter-Landsberg, 2007). HSP70 maintains
protein intact by preventing protein aggregation, actively triggers unfolding, dissolving
aggregate, pull translocation protein through membrane, and remodeling native protein complex
(Goloubinoff et al., 2007), stabilizing denatured protein, refolding reversible denatured protein
with other chaperon molecules, and facilitating degradation of irreversible denatured protein
(Tomanck et al., 2003; Brown, 2007).

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Figure 4. Release of HSP70 from cell may interact with wide target cell (Calderwood SK, 2007).

HSP70 is released from cell and interacts with many cell targets. HSP70 may be released
by active secretion mechanism or necrotized cell. Result of extracellular HSP70 (red triangle)
interacts with neuron, monocytes, or macrophages or enters the circulation. HSP70 can be
released simultaneously with antigenic peptide (blue rectangle) and HSP70 peptide complex
taken by antigen presenting cells (APC) such as dendritic cell. The peptide can be transferred to
Major histocompatibility class I molecule (darker blue rectangle) through cross presentation
process. MHC complex class-1 peptide protein is recognized by CD8+ T lymphocytes, causes T-
cell activation. Similar property may be used for other HSP (Calderwood SK, 2007). (Figure 4).

Relationship among stress, depression, and multiple system in human.

Chronic stress occurs in depression state, which causes metabolism modifications such as: a) NF-
kB activation by Toll-like receptor (TLR) during immune stimulation, leads to inflammation
response. b) Releasing of pro-inflammatory cytokines TNFα, IL-1, and IL-6. c) These cytokines
enters the brain through leaky region in blood brain barrier, active transport molecules, and
afferent nerves fibers (i.e vagal sensory) which deliver stimulus through nucleus tractus solitarius
(NTS). d) Since entering the brain, cytokines are involved in depression disorder pathway by
changing neurotransmitter metabolism of serotonin and dopamine, activate CRH pathway and
release of glucocorticoid and cortisol hormone, leads to plasticity disturbance of synapses

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through growth hormone and BDNF (Brain derived neurotropic factor) neurotropic disorder. e)
Environment exposure causes activation of NFkB inflammatory signal by increasing pro-
inflammatory sympathetic nervous system, binding of norepinephrine (NE) to α-AR and β-AR
adrenoceptors. f) Stressor inducts withdrawal of motoric inhibitory input of vagal nerve, which is
acetylcholine (Ach). Acetylcholine binds to α7 subunit from nicotinic acetylcholine receptor
(α7nAChR). g) Activation of mitogen activated protein by releasing glucocorticoid as HPA axis
response towards stress (Raison CL, 2007). (Figure 5).

Figure 5. Stress-immunity and depression interaction (Raison CL, 2007).

Conclusion
Well living needs the stability of body metabolism, called as hemodynamics. Respond of the
body for any event has effects to a whole body system, such as neurotransmitter system, which
delivers signal for physical activities, mental, and behavior, beside the autonomic nervous
system. Slowly, neuroendocrine and neuroimmune system change through various proteins.
Another substantial system is stress protein HSP70 for cell recovery from damage. There are

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several system involved such as reactive oxygen species (ROS) system, excess ROS may inhibit
protein function and trigger apoptosis. The other affected systems are intracellular, genetic, and
epigenetic system. They have harm effects and structural alterations, then clinically manifest as
physical and mental disorder. Therefore, recovery of stressor effects may not restore previous
function and structure of the neurons, but tend to trigger neuroplasticity adaptation. Intervention
such as psychopharmacology and psychotherapy is given to stimulate neuroplasticity adaptation.

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