Stress, Neuropeptides, and Systemic Disease
Adrenergic receptor activation may directly affect the insulin signaling pathway or cellular glucose transport Mulder et al. Additionally, GCs and NE could also regulate inflammation. In diabetes, elevated circulating levels of proinflammatory cytokines are originally thought to be the adipocytes themselves in response to obesity. However, an increasing number of evidence suggests that obesity results in increased number of macrophages and changes in the activation status of these cells. Therefore, adipose tissue macrophages produce a significant proportion of the inflammatory factors that are upregulated by obesity Donath and Shoelson, Inflammatory cytokines produced by various cells such as Kupffer cells, macrophages, neutrophils, monocytes, adipocytes and hepatocytes, have critical roles in lipid metabolism and hepatic inflammation that promote liver damage.
Stressful experiences are fundamental in the provocation of major depression of disorder MDD. MAPK pathways have been proved to increase the activity of serotonin membrane transporters, the most important neurotransmitter associated with depression Zhu et al. The main idea of inflammatory depression is the activation of the inflammatory immune response, particularly the synthesis of cytokines, which might influence neurochemicals and contribute to MDD Smith, Stress can facilitate the development of depressive-like behavior by promoting inflammatory cytokine expression Norman et al.
Additionally, a new pathway—kynurenine pathway KP has attracted much more attention in cytokine hypothesis. Proinflammatory cytokines activate KP to affect tryptophan metabolism and produce neurotoxin, which either reduces serotonin synthesis or fastens the reuptake of serotonin Miura et al.
Data from animal models and clinical patients prove the role of inflammation in depression. Elevated inflammatory mediators such as cytokines and their soluble receptors, chemokines, acute phase proteins, adhesion molecules and prostaglandins PGs have also been found with depression in peripheral blood, CNS and cerebrospinal fluid CSF; Miller et al. We use chronic stress to establish depression model.
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Accompanying the upregulation of proinflammatory cytokines, depressive-like behaviors were established. In fact, some clinical antidepressants really have the role of anti-inflammation. Antidepressant drug and nonsteroidal anti-inflammatory drugs NSAIDs like minocycline, decrease blood levels of IL-6, attenuate microglial activation and central cytokine secretion and behavioral changes Henry et al.
Recent research showed protective effect of caspase-1 inhibition on brain function, and gut microbiota induced depressive- and anxiety-like behaviors Wong et al. The role of stress and inflammation are being recognized in neurodegenerative disease. AD and PD are the two most common neurodegenerative diseases. PD is characterized by progressive loss of nigrostriatal dopaminergic DA neurons and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities.
The potential etiology and molecular mechanisms underlying the pathogenesis of AD and PD remains unknown and have not been completely elucidated. However, some progress has been made in identifying the risk factors. During the last two to three decades, increasing evidence from animal and clinical studies has implicated stress and neuroinflammation as risk factors and may play a fundamental part in the pathogenesis of AD and PD.
Hypercortisolemia is one of the features found in patients diagnosed of AD. Activation of the systemic innate immune system by infection may participate in the early stages of AD pathogenesis Perry et al. Neuroinflammation induces degenerative changes in the DA system, which lowers the set point toward neuronal dysfunction and degeneration Morand and Leech, Proinflammatory lipid mediators include PGs and platelet activating factor, together with cytokines may significantly affect the progressive neurodegeneration in PD Busillo et al. Mice with microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage have been used to serve as an experimental model of PD.
Stress exposure increased neuroinflammation in AD and is characterized by astrogliosis, increased inflammatory gene expression and lipid peroxidation Perez Nievas et al. It has been confirmed with the changes in glial cells surrounding the senile plaques. Genetic research demonstrates that inherited variations in inflammatory response mechanisms may influence AD pathogenesis Grimaldi et al.
In consistent with epidemiology, nicotine was proved to have a neuroprotective effect on DA neurons by means of an anti-inflammatory mechanism mediated by the regulation of microglial activation Park et al. Therefore, new potent neuroprotective therapies for PD might be taken into account by focusing on critical inflammatory mechanisms, such as cytokine-induced neurotoxicity Morand and Leech, A variety of preclinical studies have corroborated the therapeutic potential of targeting cholinergic anti-inflammatory pathway Bencherif et al.
Chronic stress has been demonstrated to account for a place in physiological and pathological disease outcomes, including several types of cancers Krizanova et al. Chronic stress is thought to correlate with the etiology of tumor growth, progression and metastasis Thaker et al. In a clinical study of breast cancer patients 3 years post-treatment, elevated levels of stress-inducible acute phase proteins correlated with an increase in morbidity and mortality in the experimental cohort Pierce et al. Furthermore, animal experiment by using daily exposure to a novel environment to explore the effect of stress on the growth rate of SC carcinoma showed that social housing condition and novelty stress may lead to various impacts on the growth rate of tumor in mice Kerr et al.
Metastasis is the main cause of death in cancer patients. Researchers demonstrated that chronic stress accelerates liver metastasis of colorectal cancer breast cancer and prostate cancer metastasis Barbieri et al. These effects were showed to have relevance with increased expression of invasion genes in tumor cells. Additionally, in some cancers e.
Among several cytokines, IL-6 is the most studied pro-inflammatory factor in tumor. Circulating levels of IL-6 have been reported as forecast cytokine of survival and metastasis in human cancers Chung and Chang, ; Salgado et al. A higher lung cancer risk for participants with elevated concentrations of IL-6 was observed in recent clinical trial Brenner et al. In animal studies, IL-6 trans-signaling is linked to tumor development in inflammation-induced colorectal and pancreatic cancer Grivennikov et al.dobgufulbiogall.ml/map12.php
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Moreover, evidence that disruption of IL-6 trans-signaling delays growth in established murine tumors demonstrates that IL-6 activities are important during neoplastic progression Grivennikov et al. IL-6 blockade would change immunological environment and reinforce the effectiveness of anti-programmed deathligand 1 anti-PD-L1 therapy, therefore evoking significant tumor suppression activity in pancreatic ductal adenocarcinoma Mace et al. Taken together, evidence linking stress to cancer progression and inflammation provide penetration into the magnitude of modulation of cancer-related cytokines e.
In summary, through disturbing the balance of immune system, stress induces inflammation peripherally and centrally. This imbalance leads to diversified stress-related diseases. Although there might be various different triggering events, they appear to converge on inflammation. In this review article, we provide evidence that stress induces or worsens CVD, NAFLD, depression, neurodegenerative disease and cancer through peripheral inflammation as well as neuroinflammation.
Therefore, we suggested that inflammation may be the common pathway for stress-related diseases, which may act as a factor that contributes disease progression or may occur very early during the development of the disease. Figure 1B shows that multifactorial factors, including genetic predisposition, aging and life style, act on stress-related diseases and that stress-induced chronic low-grade inflammation is the common soil of a wide variety of the chronic diseases.
Figure 1. Scheme for the relationship among stress, inflammation and stress-related diseases. B Stress-induced chronic low-grade inflammation might be the common soil of stress-related diseases. Multifactorial factors, including genetic predisposition, aging and life style and so on, act on stress-related diseases.
Stress-induced inflammatory response represents the common soil of a wide variety of the chronic multifactorial diseases. Stress-induced inflammation described here may be relevant to understand the common mechanisms of stress-related diseases. However, quite a few unanswered questions still need to be further discussed. For instance, besides inflammation, is there the crosstalk among inflammation and other related pathways such as cell stress? Is there the specific cell or pathway for the specific stress-related disease?
Can anti-inflammatory specifically affect neuroinflammation without modulating periphery immunity for CNS disease? More crucially, to reach clinical application, anti-inflammatory therapies will need to accurately target on specific cells and pathways in CNS, which are fundamentally important in human disease pathogenesis. All these limitations could be the next research key point. Breaking through these barriers would make great progress on the treatment of stress-related diseases. Overall, one thing is clear at present time.
To improve stress condition, reduction of psychological and physical stress should be put on the agenda of the patients with a wide variety of the chronic multifactorial stress-related diseases. Furthermore, interventions targeting stress risk factors, especially stress-induced inflammation, would be beneficial for the treatment of diseases mainly aiming at specific inflammatory factors , especially for disease prevention among the highly stressful people mainly anti-inflammation non-specially.
C-LJ designed the work and edited the manuscript. All authors read and approved the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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PubMed Abstract Google Scholar. Aparicio-Vergara, M. Tumor necrosis factor receptor 1 gain-of-function mutation aggravates nonalcoholic fatty liver disease but does not cause insulin resistance in a murine model. Hepatology 57, — Barbieri, A. The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo. Bellinger, D. Sympathetic modulation of immunity: relevance to disease. Bencherif, M. Life Sci.
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Graham, J. Stress, age, and immune function: toward a lifespan approach. Grimaldi, L. Grivennikov, S. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Many studies show that the intensity of chronic, debilitating skin symptoms such as pruritus correlate with psychopathological conditions such as depression, anxiety, dysfunctional coping behavior, dissociation, withdrawal, and helplessness 1 - 3.
Treatment is required, but frequently the necessity to address the psychosocial distress of chronically ill individuals is met by ill acceptance, a phenomenon that seems worth changing both in the medical as well as in the social context. Especially against the background of recent epidemiological and epigenetic studies, the question arises whether a causal relationship between psychosocial stress and skin is possible, or at least one that impacts disease severity.
The central topic of these research fields is the interdisciplinary scientific analysis of skin diseases in the contex of the biopsychosocial concept and psychoneuroimmunological insights. Apart from psychodermatology, workup and treatment of these disorders fall into the realm of psychiatry. Understanding this interrelation is critically relevant, not only to ensure a good quality of life of affected patients but also for consistent therapeutic success. A physician for example, who can explain how pruritus is aggravated by stress, which skin structures are involved, and which lifestyle factors may have an effect on these structures, will be taken seriously by his or her patients.
They will feel part of the diagnosis and treatment process, which increases their compliance and active contribution to the therapeutic success. A chronically ill patient who understands his or her disease and learns how to cope with it, is a grateful, cooperative, and returning patient, providing positive feed back and efficient interaction. The present review article discusses this treatment approach.
Historically, the psychodermatological approach developed when it was discovered that stress can cause increased inflammation — especially by viruses — at the epithelial surfaces of the organism. In the s, these findings initiated PNI research. One could say that allready the first PNI experiments were ultimately dermatological experiments.
Accordingly, numerous publications demonstrated that psychosocail trauma a severe loss or uncontrollable threatening experience, such as the loss of a partner or child; experiencing severe violence; and others frequently occurres prior to the onset of atopic dermatitis, psoriasis, or malignant melanoma. Also anxiety disorders and depression are often associated with skin diseases.
However, ultimately no specific disease personality structures or specific interdependencies between one or the other mental disease and a specific skin disease could be identified. Thus, researchers were unable to identify an atopic dermatitis, psoriasis, or cancer personality, and interest in this field subsided for the time being.
In the meantime, epidemiological studies have confirmed a high and rising coincidence of psychopathological diagnoses and chronic skin disorders 9. Among other things, there is evidence that a low psychosocial status is associated with an increased incidence of allergic diseases and cancer — in certain contexts even with increased mortality.
Stress, Neuropeptides, and systemic disease
Research on psychosocial factors in skin disorders is therefore once again picking up speed. A current systematic review of 16 publications links maternal psychosocial stress with atopic disorders in the child 7. The mortality in this group was compared to that of participants with lower GHQ12 score. Hence, epidemiological studies clearly show that psychosocial stress and the development of chronic and malignant diseases of the skin are linked.
It remains to be determined how exactly stress and disease are linked in a specific context, that is for a particular type of stress such as acute vs. Various idioms in the German language illustrate the close link between psychosocial distress and the state of the skin. These figurative idioms suggest specific neuroendocrine activation and it's interaction with the skin's immune system: for example, regulation of blood flow by adrenergic nerves or sensory stimulation with subsequent neuropeptide release and mast cell activation, also known as neurogenic inflammation.
So what are the exact mechanisms involved that bring experienced the stress into the body and, ultimately, under the skin? First, through its dense innervation and network of blood vessels, the skin is directly linked to central structures of the neuroendocrine stress response. These structures include the classic stress response systems of the organism such as the endocrine system and the nervous system, whose interactions have been intensively investigated by PNI research for more than 40 years 12 - Stress thereby acts as the key term which summarizes findings from many different fields.
Since Hans Selye it is defined as any challenge that requires an adaptive response. Experimentally, an acute stress response can be triggered by skydiving or an exam situation. The following components are involved in this response:. At the same time, energy is mobilized by gluconeogenesis, lipolysis, and insulin release; blood pressure rises and the perception of pain is suppressed. Obvious cutaneous symptoms include the increase in skin temperature due to an increase in metabolic rate as well as pain suppression under acute stress.
The activation of this axis is easily visible on the skin by its turning pale. Thus, adaptive responses involving the entire organism enable fight or fight. Instead, a change in the neuroendocrine profile is initiated. The release of cortisol in response to acute stressors for example is reduced, instead, baseline secretion is increased. Hence, if a chronically stressed organism encounters acute stressors, cortisol levels do not rise as much as otherwise under acute conditions, nor do they decrease as much afterwards. In a way, the stress response systems transgress to a higher level of stress responsiveness.
In the skin, the effects are complex and strongly affect neuroanatomy and the immune response, as will be discussed in the following. Getting up in the morning represents such an acute stress exposure and raises for example cortisol levels with all the aforementioned consequences. Acutely elevated and then rapidly dropping cortisol levels, which are readily detectable in sputum and serum 19 , lead for example to the activation of natural killer cells, thus innate immune mechanisms, within minutes.
The successful nonspecific defense against disruptive factors is thus the aim of an acute inflammatory response. Diseases associated with increased cellular immunity, however, show exacerbation due to the immune system's response to such stressors for example, psoriasis Figure 2. Persistent stress over a long period of time causes changes to the stress response. Morning cortisol rise declines and baseline secretion over the course of the day increases as evidence of changes to the HPA under chronic stress.
This altered pattern induces changes in the response pattern of the immune response with the aim to enable adaptation to chronic stress Figure 2. Now, cytokines are released that suppress the initial, predominantly cellular immune response. Hence, immune cells are activated which recognize and eliminate specific challenges to the immune system.
These cells are part of the adaptive immune response, especially of the humoral branch, which is responsible for antibody production 13 , 20 and permanently elevated endogenous cortisol levels lead to a shift in the immune responds towards Th2 predominance. This has advantages for the organism. An acute inflammatory response has to be turned off again once the acute challenge has been eliminated. This saves energy and avoids collateral damage caused by excessive inflammatory reactions.
At the same time, however, the innate nonspecific immune response is now suppressed, and the organism is blind to new microbes and tumor cells. Both in the lay and specialist literature, stress is often only associated with this extreme immunosuppressive effect of high doses of corticosteroids and HPA alterations while it represents only the most severe form, and occurs rarely outside treatment with corticosteroids or chronic exhaustion. It is, however, still unknown which role this observation plays with respect to the interaction between stress and skin disorders.
Apart from the described effects of the HPA, SA, and CA, mast cells seem to play a key role in excessive immunological responses to stress. Already Hans Selye, who coined the stress term, described mast cells as pivotal immune cells when it comes to recognizing disturbances microbes, toxins, physical stress at the interface between organism and environment. Only with the discovery of mediators released by sensory nerve fibers did one realize however that mast cells are in close contact with signaling nerve fibers, and thus may be activated also by psychosocial stress Until this discovery, it had been assumed that the only function of sensory nerve fibers was to sense.
Systemically, SP modifies the stress response by inhibiting the HPA; locally, by increasing sensory perception and pruritus. In an animal model, stress leads to an increased number of contacts between peptidergic nerve fibers and mast cells 24 , which subsequently results in increased mast cell degranulation. Under the influence of SP, mast cell degranulation is significantly more pronounced in response to immunological triggers such as IgE Stimulation with neuropeptides can directly prompt mast cells to release their best known secretagogue: histamine.
Hence, mast cells interacting with peptidergic nerve fibers can trigger nonspecific inflammation in response to psychosocial stress, and initiate cellular immunity. Thereby, neurotrophins supervise the interaction between mast cells and peptidergic nerve fibers under stress by regulating neuronal plasticity and contacts between nerve fibers and mast cells 28 , In case neurogenic inflammation is activated by a stimulus that is actually harmless, severe adverse effects may ensue.
An impressive example of this are anaphylactoid reactions, which are marked by an acute inflammatory response, potentially culminating in death. Clinically, this manifests as pruritus, erythema, and edema of the skin. In response to stimulus, neurogenic inflammation can thus take a visibly and perceptibly more severe course, and through this effect play a role in skin disorders, which are characterized by the respecitve symptoms.
Neurogenic inflammation illustrates quite impressively how stress mediators are able to affect the skin. All other mediators of the aforementioned stress response systems, including the transcription factors and their regulators e. NF K B , epigenetic regulatory mechanisms e. By producing mediators, which are traditionally exclusively attributed to the brain, keratinocytes, fibroblasts, sebocytes, melanocytes, Merkel cells, and endothelial cells create their own local neuroendocrine milieu. At the same time, these cells exhibit a broad spectrum of corresponding receptors and signaling cascades.
It would be beyond the scope of this article to present the complete neuroendocrine repertoire for every structural cell of the skin; for detailed and still current information, the reader is referred to other sources 11 , 13 , 33 - It is, however, important to realize that the spectrum of possible responses to stress mediators is very broad for any given skin inhabitating cell type. At the same time, they also have receptors for all of these stress mediators.
Thus, by producing cortisol, keratinocytes can play a role in wound healing 43 as well as in tumor growth and chronic inflammation, both in an autocrine and a paracrine fashion. In case of chronic cortisol exposure, however, the corticosteroid receptors may be epigenetically regulated by methylation, resulting in cellular desensitization. The systemic stress response is thus complemented by a local stress response. An analogous and reciprocal, pathogenetically relevant relationship between chronic psychosocial stress and chronic immunologically mediated diseases can therefor be assumed.
In the long run, however, it can barely be clinically distinguished from endogenous depression. Various stress mediators mutually influence each others central effects. For example, SP slows down the HPA response, which can accelerate the switch towards a chronic stress response in the brain. Immunocytes matured in peripheral lymphatic organs also contribute to the modification of the central stress response. For example, peripherally derived monocytes which trigger anxiety behavior are found in the brains of stressed mice Anamnestic assessment of patient's biographical history identifies traumatic life events, which show high coincidence with atopic dermatitis, psoriasis, or skin tumors, and usually occur within approximately six months prior to the onset of the skin disease.
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