Role of stress in skin diseases: A neuroendocrine-immune interaction view

the release of pro-inflammatory cytokines, thereby exacerbating existing skin diseases such as psoriasis, atopic dermatitis, acne, and urticaria. In the present review, we explored the intricate relationship between stress and skin diseases from a neuroendocrine-immune interaction perspective. We explored the occurrence and development of skin diseases in the context of stress, the stress models for skin diseases, the impact of stress on skin function and diseases, and relevant epidemiological studies and clinical trials. Understanding the relationship between stress and skin diseases from a neuroendocrine-immune interaction perspective provides a comprehensive framework for targeted interventions and new insights into the diagnosis and treatment of skin diseases.


Introduction
Stress is a common condition worldwide, and people experience severe public mental health challenges, such as social distance, isolation, fear, loneliness, loss of family or friends, unemployment, and financial instability, leading to psychological stress (Wang et al., 2022).Psychological stress plays an important role in activating and promoting the development of diseases, such as inflammatory bowel disease, obesity, and cancer, through neurological, metabolic, and immune pathways (Bisgaard et al., 2022;Eckerling et al., 2021;Tomiyama, 2019).Stress has been considered a crucial factor affecting the incidence and progression of skin diseases for decades (Alexopoulos and Chrousos, 2016); however, no unanimous conclusion has been reached through epidemiological data and clinical trials to clarify the impact of stress on skin diseases.
There has been an increasing number of studies on the influence of stress on skin diseases in recent years.Researchers are exploring deeper into the complex relationship between psychological well-being and dermatological health.Notably, several studies have reported significant associations, such as depression being associated with a heightened risk of skin conditions like dermatitis, eczema, alopecia areata (AA), and urticaria (Criado et al., 2022;Ferentinos et al., 2022;Leone et al., 2021;Shen et al., 2021).In addition, the coronavirus disease 2019 (COVID-19) pandemic brought the impact of psychological stress on skin health to light, with individuals under stress experiencing more severe psoriasis (Kuang et al., 2020).A prospective cohort study on psoriasis reported significant improvement in stress-related parameters, such as amygdala activity, in patients with severe psoriasis compared with healthy volunteers (Goyal et al., 2020).The findings emphasize the importance of addressing stress management as a crucial component of overall skin care and well-being.Furthermore, stress aggravates the itching sensation of skin diseases through mast cell (MC) activation (Golpanian et al., 2020).Stress can also affect biological behaviors, such as tumor initiation, progression, and metastasis, and promote immune evasion of tumors by inhibiting the immune system (Eckerling et al., 2021).Currently, stress is recognized as a predisposing factor for skin diseases such as psoriasis, AA, and atopic dermatitis (AD) (Griffiths et al., 2021;Langan et al., 2020;Pratt et al., 2017); therefore, elucidating the relationship between stress and skin diseases is necessary.
Stress is defined as a negative emotional experience accompanied by the triggering of affective responses (such as anxiety) and alteration of the functions of the hypothalamic-pituitary-adrenal (HPA) axis and other regulatory and neuroendocrine systems (such as gonadal steroids), implicating disease onset and severity (Baum, 1990;Cohen et al., 2016).Stress and skin diseases can be associated through various mechanisms, as various forms of stress can facilitate the development of skin diseases.The stigma caused by skin diseases may further increase the psychological burden, forming a vicious cycle of psychological stress leading to skin diseases (Fig. 1).Therefore, the present review aims to investigate the impact of stress on skin diseases.

Overview of stress
Stress is a collective term referring to a series of physiological responses to threats (Selye, 1936).Stress can be classified according to various factors; for example, it can be classified into acute and chronic stress based on the onset and duration, mild, moderate, and severe stress based on the intensity of exposure, and positive and negative stress based on personal experience (Koolhaas et al., 2010).Hans Selye, known as the "father of stress research," described stress in three stages based on its characteristics: non-specific mobilization, promotion of sympathetic nervous system activity, and resistance stages (Selye, 1936).The process from the receipt of stress signal to the response can be completed through the neuroendocrine-immune (NEI) pathway.
The brain is a stress receiver and initiator of stress responses.The HPA axis is activated by corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (PVN) (Miller, 2018).
Under stress, the interaction network between the anterior cingulate cortex (ACC) and medial prefrontal cortex (PFC) regulates the autonomic and neuroendocrine effector pathways, thereby regulating inflammatory responses (Ulrich-Lai and Herman, 2009).Furthermore, brain regions such as the hippocampus, amygdala, and ventral tegmental area are also involved in stress responses (Du Preez et al., 2021;Kim and Cho, 2020;Xu et al., 2021).
The brain initiates stress response and then transmits information to the periphery through various mediators such as glucocorticoids (GC), norepinephrine, and neuropeptides to complete the delicately planned physiological responses (Deussing and Chen, 2018).The brain also regulates other endocrine mediators involved in peripheral immune processes, such as prolactin, oxytocin, and opioids (Carter et al., 2020;Moyano and Aguirre, 2019;Wu et al., 2014).These mediators bind to various receptors located on different types of immune cells to produce specific effects (Chu et al., 2020;Pavlov and Tracey, 2017;Yang et al., 2023).
Neurotransmitters induce various immune responses, including cell activation, differentiation, motility, and apoptosis (Chen et al., 2021a).For example, adrenergic receptor ligands are most abundantly expressed on immune cells, and β2-adrenergic receptors (ADRB2) signaling can inhibit dendritic cells (DCs), T cells (Estrada et al., 2016), and innate lymphocytes (Moriyama et al., 2018), which may be associated with the immunosuppressive function of β-adrenergic signaling, including inhibition of nuclear factor kappa B pathway activation and induction of immunosuppressive cytokine production (Agaç et al., 2018;Pavlov and Tracey, 2017).ADRB2 activation facilitates anti-inflammatory macrophage development (Grailer et al., 2014), whereas the activation of α-adrenergic receptors increases the production of tumor necrosis factor (TNF) in macrophages (Huang et al., 2012).The effect of stress should not be analyzed separately but in combination with the action of the NEI network, which synchronizes with body behaviors (Fig. 2).
The relationship between stress and non-psychoneurotic disorder has gradually been revealed recently.Epidemiological analysis suggests that stress is associated with the development and progression of chronic inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease (Bisgaard et al., 2022;Herrmann et al., 2000).Psychological stress leads to increased cortisol levels and norepinephrine release, which alter enteric nervous system activity to promote intestinal inflammation through effects on intestinal permeability, mucin production, and immune cell function (Schneider et al., 2023).Furthermore, stress promotes dectin-1-dependent interleukin (IL)-17 production by colonic γδ T cells through a pathway involving CRH-induced MC release of IL-33, leading to intestinal inflammation (Zhu et al., 2023).However, only a few studies have explored the mechanism underlying the relationship between stress and skin diseases, and there are still limitations to the overall concept of central-mediatortarget cells.Therefore, summarizing the current studies on stress and skin diseases is necessary.

Stress models applied to skin diseases
Animal models play an important role in the study of the pathogenesis of stress-related mental disorders and corresponding treatment strategies.The negative effects and mood in cases of mental disorders can also be observed in animal models.Stress models have been widely used in studies on systemic inflammation, type 2 diabetes, obesity, and tumors.Herein, we summarized the commonly used stress models and their evaluation methods (Fig. 3), and the commonly used methods for establishing skin disease-related stress models are presented in Box 1.

Fig. 1.
The vicious cycle between psychological stress and skin diseases: Psychological stress can activate the interaction between the nervous system, endocrine system and immune system in the body, forming a neuro-endocrineimmune network to promote the onset and development of skin diseases, and the stigma caused by skin diseases further aggravates the psychological burden of patients, thus forming a vicious cycle of psychological stress-skin diseases.Abbreviation: HPA, hypothalamic-pituitary-adrenal.

Fig. 2. The circuit of body response to stress:
The signal of stress is first received by the brain, and information is transmitted to the periphery through a variety of mediators after initiation of the stress response, which mainly involves the HPA axis, sympathetic nervous system, and released hormones and peptides, which bind to the corresponding receptors on cells through a series of pathways.The cells involved in the effector phase include immune cells (T cells, B cells, and macrophages) and immune-related cells on the skin (mast cells, denteitic cells, keratinocytes), which jointly participate in the body's immune response to stress and form the body's NEI network.Abbreviation: HPA, hypothalamic-pituitary-adrenal; NEI, neruoendocrine-immune.

Fig. 3.
Stress model of skin diseases and its evaluation: Currently, the stress modeling methods for skin diseases mainly include CRS, UCMS, CSDS, and LH, which require varied length of time to establish.The specific modeling methods can be determined according to the corresponding indicators.After stress modeling, animals with the anxiety and depression phenotypes can be obtained.Anxiety is mainly measured using their tension, with main behavior detection methods being EPM, OFT and LDB; depression is mainly evaluated using the loss of pleasure and the reduction of survival skills, with the main behavior detection methods being FST, TST and SPT.Abbreviation: CRS, chronic restraint stress; UCMS, unpredictable chronic mild stress; CSDS, chronic social defeat stress; LH, learned helplessness; EPM, elevated plus maze; OFT, open field test; LDB, light dark box; FST, forced swimming test; TST, tail suspension test; SPT, sucrose preference test.

Chronic restraint stress
Research on the application of chronic restraint stress (CRS) to skin diseases has shed light on the relationship between psychological stress and skin health.CRS is a non-injurious stress model established by inducing long-term social and environmental stress in animals to produce typical depression-like behaviors; therefore, it can be used to establish highly operable and reproducible animal models of depression (Zhao et al., 2013).The establishment of this model requires a single mode of stimulation to experimental animals for a varying period (10-21 days).Studies have reported that CRS can cause anxiety and depression-like behaviors in rats through damage to the ACC and hippocampus and degeneration of amygdala neurons and astrocytes (Xu et al., 2019).CRS is a chronic and predictable form of stress, and its establishment is relatively simple; therefore, CRS models are widely used in studies on stress-related mental disorders.

Unpredictable chronic mild stress
Unpredictable chronic mild stress (UCMS) is a modeling method in which experimental animals are treated with such stress for a long time and exhibit emotional changes under unpredictable conditions (Willner et al., 1987).Because its pathogenesis is similar to the mechanism of depression, it is widely used by researchers worldwide (Alqurashi et al., 2022;Ayuob et al., 2022).UCMS reduces the level of GC receptors and the density of the myelinating cells such as oligodendrocytes and inhibits the expression of brain-derived neurotrophic factors (BDNF), phosphorylated transcription factor cyclic adenosine monophosphate Box 1 Specific details of stress models of skin diseases.

Chronic restraint stress (CRS)
Chronic restraint stress is achieved by confining the mice in a restraint bucket for a certain period of time each day, causing them to become anxious and depressed.The time of restraint is 2 h per day for 14-21 days, with the number of days and duration of restraint per day being adjusted based on the purpose of the experiment and the specific circumstances during the experiment (Liu et al., 2020;Zhang et al., 2019).CRS has been used in studies of a variety of skin diseases.After treating different mouse strains (C57BL/6, CBA/J, C3H/HeN line, BALB/c and ICR) with chronic stress for 21 days, it was found that CRS might inhibit the hair follicle growth and melanogenesis, which was associated with the HPA axis, with C57BL/6 mice being most sensitive to CRS (Wang et al., 2018).Some other studies found that decreased hair follicular melanogenesis might be related to changes in hippocampal morphology (Liao et al., 2017).CRS may also lead to abnormal hair cycles by inducing autophagy (Wang et al., 2015).It has been reported that CRS might have affected their skin health by changing the composition of fatty acids and the concentration of amino acids (Kitagawa et al., 2022).Overall, studies on the application of CRS to skin diseases have highlighted the detrimental effects of chronic stress on skin health.The findings emphasize the importance of managing and mitigating stress in individuals with pre-existing skin conditions or at a high risk of developing them.

Unpredictable chronic mild stress (UCMS)
UCMS is a widely used method of modeling by which experimental animals are treated with such stress for a long time so that they have emotional changes under unpredictable conditions (Willner et al., 1987).This type of treatment can cause lasting changes in animal behaviors, gut microbiota, and neurological function (Antoniuk et al., 2019).The UCMS model can be established using gentle stimuli such as tilting cages, humid bedding, cohabitation, and hot water swimming, with sucrose solution consumption (which reflects anhedonia) used as a core marker of successful modelling (Remus et al., 2015;Xu et al., 2017).Compared to CRS, UCMS modeling is more complicated, with variability and unpredictability of the stimuli being key to the success of modeling.It has been found that UCMS modeling for 21 days could result in abnormal dorsal pigmentation among C57BL/6J mice, which might be mediated by 5-HT1A/1B receptors and could be used as a target for the treatment of skin pigmentation disorders, especially after stress-related experience; it was also speculated that fluoxetine might be used as a potential treatment approach for hypopigmentation disorders (Wu et al., 2014;Zhou et al., 2018).Upregulation of proinflammatory cytokines such as TNF, IL-6 and inducible nitric oxide synthase as well as downregulation of malondialdehyde, superoxide dismutase, glutathione peroxidase and catalase were detected in rats exposed to UCMS for 4 weeks and then to 1-fluoro-2,4-dinitrofluorobenzene (DNFB) for 2 weeks, which could aggravate the contact dermatitis (Ayuob et al., 2022).UCMS can also regulate the expression of serotonergic receptors in the cerebellar cortex of atopic mice (Rasul et al., 2013).The impact of UCMS on skin physiology and disease progression has improved our understanding of the intricate interplay between psychological stress, immune responses, and skin health and highlighted the importance of stress management and targeted interventions in individuals with skin diseases.

Chronic social defeat stress (CSDS)
CSDS is a rodent resident-intruder paradigm based on the relationship between "bullies" and "victims" in the human society (Björkqvist, 2001).In this model, animals present with social avoidance (known as susceptible mice) or normal behaviors (known as resilient mice) (Golden et al., 2015).To establish the CSDS model, 6-8-week-old male C57BL/6J mice are selected as experimental animals and retired male CD-1 breeder mice are selected as original residents.Before establishment of the model, the male CD-1 breeder mice need to be kept in a separate cage for at least 7 days to develop their territoriality, and the mice with at least three consecutive attacks or a latency of less than 30 s are selected.The C57BL/6J mice will then be placed into the cage of CD-1 mice to allow for their exposure to the attacks by the latter for 5-10 min.During this period, the C57BL/6J mice will present with behaviors or states such as panicking, escaping, rigidity and screaming.The two types of mice will then be separated using a transparent divider with holes for 24 h to prohibit their direct contact but enable them to see and smell each other.This process is repeated for approximately 10 days to enable the C57BL/6J mice to expose to the attacks by different CD-1 mice, which ultimately leads to depression-like behaviors of the former (Golden et al., 2011;Golden et al., 2015).It has been found that, after CSDS in OF1 mice was inoculated with B16F10 melanoma cells, the mice exhibiting passive/reactive coping strategies develop more pulmonary metastases at the end of the social stress treatment, as compared with those in other groups that had higher in vivo corticosterone levels (Goñi-Balentziaga et al., 2020); furthermore, AD-like mice exposed to CSDS showed downregulation of DNA methyltransferase 1 and upregulation of C-C chemokine receptor type 7 in skin DCs, as well as aggravation of scratching behaviors associated with dermatitis and itching (Yoshida et al., 2020).These findings highlight the importance of considering social stressors and their impact on skin physiology in the management and treatment of skin diseases.Targeted interventions aimed to mitigate the negative effects of chronic social stress may be promising in improving skin health and managing skin conditions associated with psychosocial stress.response element-binding protein, and phosphorylated extracellular signal-regulated kinase in the cornu ammonis (CA)1, CA3, and dentate gyrus areas of the hippocampus, thereby causing depression (Chen et al., 2019;Qiao et al., 2020).UCMS is an animal model that involves the exposure of animals to a series of unpredictable and mild stressors over an extended period.Studies utilizing the UCMS model have demonstrated its ability to induce or exacerbate various skin disorders, including AD and psoriasis (Rasul et al., 2013) (Box 1).As a chronic and long-term form of stress leading to cognition and memory impairment, UCMS is a good simulation of the pathogenesis of depression and other stress-related mental disorders in humans.

Chronic social defeat stress
Chronic social defeat stress (CSDS) is based on social struggles; the model is established by inducing emotional, psychological, and mental stress in defeated animals, ultimately inducing social withdrawal and anhedonia (Menard et al., 2017).CSDS can lead to increased levels of cytokines, such as IL-1β, IL-6, and TNF, intestinal dysfunction, hippocampal microglial activation, decreased expression of free fatty acid receptor 2 and 3 genes, and increased expression of tight junction proteins (Tian et al., 2019).Studies utilizing the CSDS model have demonstrated its ability to induce or worsen various skin diseases (Goñi-Balentziaga et al., 2020;Yoshida et al., 2020).In this model, social stressors simulate the psychosocial challenges experienced by humans, allowing researchers to investigate the impact of chronic social stress on skin physiology and pathology.Currently, the pathogenic factors of depression are still being explored.Exposure to stressors remains the primary factor, and long-term and excessive exposure to stressors can cause mental health problems.Therefore, the CSDS model is an important tool to study depression-like behaviors caused by social frustration.

Other stress models
The model of learned helplessness is established by placing the experimental animal in an unpredictable and uncontrollable stressful environment.After experiencing stress, the animal exhibits reduced learning and spontaneous activities, they become aware of the uncontrollable stimulation, and then produces negative emotions, somewhat similar to depressive symptoms in humans (Brachman et al., 2016).Notably, some studies have reported that hair growth in learned helplessness-treated rats is significantly associated with elevated corticosterone levels and more depression-like behaviors (Ren et al., 2021).The early life stress model is a mother-infant separation model of early stress; it is built under the principle that adverse events in early life can lead to the development of mental illness in late life (Murthy and Gould, 2018).Models can also be established based on gene mutations (Howard et al., 2019) and drug-induced stress (Sens et al., 2017); however, these approaches are less commonly used in recent studies on skin diseases.Notably, none of the existing animal models produced symptoms of mental disorders identical to those in humans, and this can be fundamentally attributed to the differences in the mental activities between animals and humans.

Evaluation of stress models
After successful modeling, experimental animals exhibit symptoms such as anhedonia and depressed mood and other depressive symptoms such as sleep disorders, weight/appetite changes, anxiety, and social withdrawal, similar to the symptoms of major depressive disorder in humans (Kendler, 2017).Generally, anhedonia can be assessed using sucrose preference tests (SPT); the experimental animals can choose between ordinary tap water or tap water containing sucrose, and those with a decreased preference for sucrose are considered to have anhedonia (Liu et al., 2018).Sexual behavior can also be used to assess anhedonia in animals; however, the evaluation, which is mainly based on males' absence of interest, is complicated for female rodents.Common tests for assessing hopelessness-related behaviors include the forced swimming test (FST) and tail suspension test (TST), in which rodents are placed in an uncomfortable and unescapable environment (water tank or positions in which animals are hung up by their tails).They demonstrate positive behaviors (swimming or struggling) at the beginning, and as they become aware that this situation is inevitable, they subsequently exhibit depression-like behaviors such as significant immobility (Porsolt et al., 1977).The open field test (OFT), elevated plus maze, and light-dark box (LDB) are used to assess anxiety-related behaviors in rodents (Borbély et al., 2017); these models are established by utilizing the conflict between the exploration of nature and the external environment, which induces anxiety, or by utilizing the emotional adaptive responses produced by animals when faced with inevitable or impending aversive stimuli (Gould et al., 2009).Physiological and pathophysiological tests, such as those involving HPA axis-related mediators, monoamine neurotransmitters, BDNF, and inflammatory factors in blood, can also be used to determine successful modeling (Kehne and Cain, 2010;Pu et al., 2021).
Stress models used in recent studies on skin diseases are mainly CRS and UCMS models.Repeated exposure to stress can result in behaviors such as reduced exploration in the light compartment in the LDB, diminished total locomotion and exploration in the central area of the OFT, and reduced sucrose preference in the SPT.Because both models are applied simultaneously, whether they both affect the final models must be considered.For example, mice can exhibit wet fur after CRS treatment; however, whether this affects certain drug-treated skin disease (such as AD and psoriasis) models remains unclear.The timing of skin disease and stress modeling should be considered, including which modeling should be performed first on the same day and how long the interval between the two modeling procedures should be, as these are best for establishing a skin disease-related stress model.The modeling of physical contact with stress may stimulate the morphological changes of tumors, such as ulcerative changes, in mice with subcutaneous tumors.Guinea pigs are also commonly used in preparing pigmented skin disease models, and related methods for stress modeling may be correspondingly changed based on the physiological characteristics and life habits of guinea pigs.

Stress and skin diseases
Brain imaging studies have revealed that limbic regions, such as the amygdala and hippocampus, show altered activities in response to psychological stress and may be implicated in stress-induced skin disease exacerbations (Hermans et al., 2011).Stress also modulates activity in the sensory cortices associated with pain perception, which may amplify skin discomfort (Lu et al., 2022).Furthermore, stress reduces connectivity between higher cognitive centers (such as PFC) and regions like the periaqueductal gray that modulate itch and pain (Gao et al., 2019;Zhang et al., 2021a).Stress-induced central nervous system changes dysregulate brain regions involved in emotional, sensory, and cognitive processing, promoting symptoms of various skin disorders.The recent studies on brain regions involved in skin diseases are presented in Table 1.Further research is needed to fully map the detailed brain circuits underlying this stress-skin disease connection.
When stress-related brain regions are activated, they can impact the skin through multiple pathways, including the HPA axis, neuropeptides, and the sympathetic nervous system (Fig. 4).The disruption of the skin's physical and immune barriers becomes an initiating factor in stressinduced skin disease exacerbation.Psychological stress triggers the release of cortisol through the HPA axis, disrupting skin barrier function (Berdyshev et al., 2018;Kim et al., 2023), impairing keratinocyte differentiation (Lee et al., 2021), increasing the risk of skin infections (Maarouf et al., 2019), and potentially exacerbating conditions such as AD and chronic urticaria (CU) (Peters et al., 2014) (Fig. 4).Peripheral nerves can influence skin health through nerve growth factor (NGF) and H. Zhang et al. other neuropeptides (Peng et al., 2013;Zhang et al., 2020).Furthermore, prolonged activation of the physiological stress response due to mental stress factors can lead to chronically elevated stress mediators in circulation, which are associated with the immune system.The immune system of the skin, comprising resident and recruited innate and adaptive components, collaborates with various skin cells to bolster the body's defense against external threats (Kobayashi et al., 2019).This intricate system is closely associated with individuals' psychological stress and mental state, influencing their skin response to stressors.To better understand the mechanisms through which stress affects skin diseases, we summarized the impact of stress on MCs, DCs, lymphocytes, and other cells associated with the skin's immune system, such as keratinocytes, as shown in Table 2.
There is a close relationship between the skin and the brain, as skin tissues and the nervous system originate from the ectoderm (Jameson et al., 2022).The skin and the brain communicate through a network called "the skin-brain axis," which allows the brain to respond to psychological stress by affecting the skin and its physiology to send signals back to the brain by producing substances that modulate the immune and nervous systems (Fregoso et al., 2021;Weiglein et al., 2022).The interaction between psychological stress and skin diseases is bidirectional; stress can worsen skin problems, which can result in mental health problems, initiating a vicious cycle.Understanding the pathophysiological mechanism underlying the association of stress with the progression of pre-existing skin diseases and the development of new skin diseases can provide a basis for clinical interventions to relieve disease symptoms and delay disease progression.Therefore, we summarized the NEI network between stress and skin diseases from prior studies to elucidate the mechanism underlying the connection between the two conditions.In this section, we summarize how stress influences skin diseases through the NEI network, which may help us better understand the relationship between stress and skin diseases.

Allergic skin diseases
Psychological stress worsens the symptoms of many allergic skin conditions, such as AD, contact dermatitis, and urticaria (Lara-Marquez and Kelley, 2020).Stress activates the HPA axis, leading to increased GC, which can damage the skin barrier, making it more permeable to allergens and irritants (Jiang et al., 2019;Slominski, 2007) (Fig. 4).MCs play a central role in the pathogenesis of allergic skin diseases (Jain et al., 2019).Psychological stress exacerbates allergic skin diseases by directly promoting MC activation and degranulation by releasing cortisol, catecholamines, neuropeptides, and NGF (D'Costa et al., 2019;Gupta and Harvima, 2018;Hendriksen et al., 2017), and among these factors, the study of calcitonin gene-related peptide (CGRP) and substance P (SP) is more concerned.Studies have shown that psychological stress can trigger the release of CGRP from sensory nerves in the skin (Rosenkranz et al., 2013).Then CGRP binds to receptors on keratinocytes and MCs, triggering vasodilation, secretion of proinflammatory cytokines, and mast cell degranulation (Steinhoff et al., 2022;Zhang et al., 2021b), which worsen symptoms and flare-ups in stress-reactive skin diseases such as AD and CU.SP, which is associated with the severity of negative emotions, is upregulated in the lesions of various skin diseases (Fried et al., 2005;Lönndahl et al., 2019), indicating that SP plays a key role in stress-related skin diseases.Dong et al. discovered a new receptor on MCs, Mas-related G protein-coupled receptor (Mrgpr) B2, which mediates anaphylactoid reactions to drugs and other substances not recognized by immunoglobulin (Ig) E antibodies (McNeil et al., 2015).They also found that MrgprB2/X2 signaling is the primary mechanism underlying the regulation of pain, inflammation, and pruritus by MCs (Meixiong et al., 2019;Meixiong et al., 2020;Serhan et al., 2019).The SP/MRGPR axis plays an important role in the mutual regulation between MCs and skin peripheral nerves, indicating that it might be a new target in treating stress-related skin diseases.In addition, the cutaneous neuroendocrine system can contribute to inflammatory diseases through MCs using CRH.The influence of stress on MCs is presented in Table 2.

Atopic dermatitis
AD is a common skin disease influenced by genetic, environmental, and immunologic factors and psychological stress (Birdi et al., 2022;Ständer, 2021).Research links stress to AD, indicating that patients with AD often experience high levels of anxiety and depression (Rønnstad et al., 2018).In addition, more frequent stressful life events have been associated with increased disease severity (Suárez et al., 2012).Stress can trigger or aggravate AD through the NEI network, and the relevant mechanisms are summarized as follows.
Stress triggers the release of peripheral nerve signaling, exacerbating AD.AD-induced mice exposed to 24 h of noise stress showed increased MC degranulation and NGF expression and more SP + fibers in contact with MCs (Pavlovic et al., 2008).A positive correlation was found between the number of MCs, the density of nerve fibers, and the chance of contact between NGF + NF and MCs in skin lesions before and after skin biopsy in AD-induced animals that underwent trier social stress test (Peters et al., 2014).Trypsin released by MCs activates proteaseactivated receptor-2 on nerve fibers, subsequently leading to the release of SP and CGRP and enhancing neurogenic inflammation (Buhl et al., 2020).What's more, keratinocytes stimulated by neuropeptides like SP and NGF release proinflammatory cytokines including thymic stromal lymphopoietin (TSLP), IL-1β, IL-6, and TNFα.These amplify skin inflammation in AD (Steinhoff et al., 2022;Zhang et al., 2021b).Furthermore, sensory neurons stimulate DC production of TSLP, promoting Th2 inflammation (Flayer and Sokol, 2022).Cortisol also

Table 1
The association between brain regions and skin diseases.
suppresses neutrophil antibacterial activity by NETosis (Pan et al., 2023), which lead to reduced and dysfunctional neutrophil responses, compromising antimicrobial defense against secondary infections in AD lesions (Fig. 5).Furthermore, the significance of the brain-skin axis in the relationship between stress and AD should be recognized.MC903-induced ADlike mouse models showed anxiety and depression phenotypes with increased serum corticosterone and BDNF, decreased tyrosine hydroxylase, and reduced expression of dopamine D1 receptor protein in dopaminergic brain regions such as the nucleus accumbens (NAc), dorsal striatum, and ventral tegmental area (Yeom et al., 2020).Kitagaki et al. found that itching behaviors and plasma IgE levels in AD-induced mice can be improved by relieving social isolation (Kitagaki et al., 2014).Yu et al. further investigated that itching behaviors after observing conspecific itching could increase neuronal activities in the suprachiasmatic nucleus (SCN) of the hypothalamus, while the contagious itching behavior disappeared after the ablation of the gastrinreleasing peptide receptor (GRPR) or GRPR neurons in the SCN, indicating that GRP-GRPR signaling is necessary for the transmission of the contagious pruritus information in the SCN (Yu et al., 2017).Furthermore, a comparison of brain processing of histamine-induced pruritus between patients with AD and healthy participants showed that the ACC and anterior and posterior insular cortices were activated in patients with AD (Ishiuji et al., 2009).Activation of the middle cingulate cortex has been associated with increased perception of itching in patients with AD; it is also associated with the itching behavior in healthy controls, and the activation can be enhanced in patients with chronic itching (Mochizuki et al., 2015;Napadow et al., 2014).Therefore, the middle cingulate cortex may be involved in itching behaviors in response to stress-induced itching.Gunhyuk et al. assessed AD-induced mice using 2,4-dinitrochlorobenzene or corticosterone to mimic stress and found elevated serum levels of dopamine β-hydroxylase and tyrosine hydroxylase, activation of the HPA axis, and dysregulation of dopamine and norepinephrine in the coeruleus, PFC, and striatum (Park et al., 2018).Using a mouse model for pruritus established with acetone-ether-water, Zhao et al. found that mice developed anxiety and depression phenotypes after LDB and FST and that there were changes in the level of HPA axis-related molecule mRNA transcript in regions such as the PVN, pituitary gland, frontal cortex, hippocampus, amygdala, and NAc.They also found that long-term treatment of acetone-diethyl-ether-waterinduced pruritus in mice with CRFR1 antagonist could improve mood disorders and stress axis dysfunction (Zhao et al., 2018).

Chronic urticaria
CU causes itchy wheals and sometimes angioedema for > 6 weeks (Zuberbier et al., 2014), and the risk of CU can be increased by stress.A study reported that patients with CU scored higher in the Urticaria Activity Score 7 (UAS7) during the COVID-19 epidemic than before.The UAS7 score was also positively associated with depression, anxiety, and stress (Beyaz et al., 2021).CU also affects the psychosocial well-being of patients by reducing their quality of life and sleep quality and impacting their emotional sensitivity; disease severity is associated with poor mental health and reduced quality of life (Choi et al., 2020;Tzur Bitan et al., 2021).
The exact mechanism through which stress affects urticaria remains unknown.CU may result from interactions between the immune and nervous systems, where MCs are activated through the HPA axis, autonomic nervous system, and local cutaneous nerve fibers (Bansal and Bansal, 2019;Sperber et al., 1989).Stress also induces the release of SP and CGRP from sensory cutaneous nerves, causing pruritus and MC activation through receptors such as the Mrgpr family, transient receptor potential ankyrin 1, and Par2.Subsequently, immune activation and skin inflammation are promoted by cytokines such as interferon (IFN)-γ, IL-4, TNF, and IL-10 (Choi and Di Nardo, 2018).Notably, several studies suggest that the interaction between MCs and neuropeptides can aggravate CU under stress; however, this mechanism requires further investigation before becoming a reliable target for CU treatment (Chen and Lyga, 2014;Konstantinou and Konstantinou, 2020).Furthermore, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3inflammasome is activated under stress, leading to increased release of pro-inflammatory cytokines IL-1β and IL-18, which mediate the association of psychological factors and mood changes with urticaria (Kaufmann et al., 2017).Estrogen and progesterone may also increase the incidence of spontaneous CU among women by stimulating autoimmunity (Assad et al., 2017).

Psoriasis
Psoriasis is a chronic inflammatory skin disorder that affects approximately 125 million people worldwide (Armstrong and Read, 2020).It is associated with physical and psychological burdens, as visible lesions can trigger negative reactions and stigma, leading to anxiety, depression, low self-esteem, and impaired quality of life (Rigas et al., 2019;Snast et al., 2018).Psychological stress has been associated with the onset and exacerbation of psoriasis, as stress can modulate the NEI network, leading to increased levels of catecholamines, GCs, and opioids, affecting the balance of T helper (Th) 1/Th2/Th17/Treg cells and cytokines involved in the pathogenesis of psoriasis (Alesci et al., 2022;Martins et al., 2020) (Fig. 5).
The core of psoriasis pathogenesis under stress is the release of mediators, such as neuropeptides, through the activation of the nervous system resulting from chronic interactions between the skin immune system, hyperproliferative and dysfunctional keratinocytes, and infiltrating activated immune cells (Hawkes et al., 2017;Rendon and Schäkel, 2019).Stress can activate peripheral nerves located in the skin, leading to the release of neuropeptides by peripheral nerve endings, including SP, CGRP, pituitary adenylate cyclase-activating polypeptide, and NGF, thereby activating MCs, leading to neurogenic inflammation (Cȃruntu et al., 2014).In addition, stress leads to the activation of the HPA axis and subsequent release of stress hormones, and CRH can enhance MC degranulation with CRH receptors on MC (D'Costa et al., 2019) (Fig. 5).Elevated serum CRH levels are also associated with the induction of vascular endothelial growth factor (VEGF) release by MCs (Vasiadi et al., 2012).VEGF is a growth factor involved in psoriasis pathogenesis and is released by activated MCs through CRH (Alexopoulos and Chrousos, 2016).Psychological stress may result in the reduction of BDNF in patients with psoriasis, and relevant animal studies have reported that BDNF can respond to stress by inducing keratinocyte apoptosis (Brunoni et al., 2015;Truzzi et al., 2011).5-hydroxytryptamine (5-HT) is a neurotransmitter involved in various brain functions, such as emotions, cognition, stress, and anxiety (Moncrieff et al., 2022).Low 5-HT levels can lead to increased TNF and IL-1β levels and induce keratinocyte activation through NF-kB and IL-17A in the PFC and hippocampus, thereby aggravating the symptoms of psoriasis (Ronpirin and Tencomnao, 2010;Shajib and Khan, 2015).Wu et al. found that the expression of BDNF and Tropomyosin receptor kinase (TrK) B decreased in the PFC and hippocampus of mice with psoriasis, and this alteration and skin lesions could be improved by fluoxetine, indicating that the BDNF/TrkB/5-HT system played a crucial role in psoriasis-associated depression or anxiety (JiaWen et al., 2018) (Fig. 5).3,4-dihydroxyphenylacetic acid (DOPAC) and norepinephrine in the PFC, 5-HT, epinephrine, and DOPAC in the hippocampus, and epinephrin and γ-aminobutyric acid in the hypothalamus were significantly decreased in mice with imiquimod-induced psoriasis (Guo et al., 2020).

Skin tumors
Stress can increase the risk of cancer onset and progression, and recent animal experiments have confirmed that stress can promote the growth, metastasis, and drug resistance of different types of cancers (Eckerling et al., 2021).However, little is known about the mechanisms underlying the relationship between stress and skin tumors.Herein, we summarized the existing studies as follows (Fig. 6).
Stress can influence the development of skin tumors by suppressing anti-tumor immunity and promoting an inflammatory microenvironment.GC signaling inhibits effector CD8 + T cell differentiation and promotes the development of dysfunctional/exhausted CD8 + T cells in the tumor microenvironment of melanoma (Acharya et al., 2020).Liu et al. found that psychological stress promotes D2 dopamine receptor (DRD2) and hypoxia-inducible factor 1-alpha (HIF1α) expression in melanoma, enhancing epithelial-mesenchymal transition through competitive DRD2/HIF1α binding to von Hippel-Lindau and impaired HIF1α degradation (Liu et al., 2021) (Fig. 6).Xu et al. found that the serum concentration of α-melanocyte-stimulating hormone was elevated in tumor-bearing mice with B16F10, and myeloid hematopoietic cell proliferation was promoted through melanocortin 5 receptorextracellular signal-regulated kinase-signal transducer and activator of transcription 3, eventually leading to an increase in tumor-associated myeloid cells and inhibition of anti-tumor immunity (Xu et al., 2022).However, Kayl et al. found that mice implanted with B16F10 melanoma tumor cells under restraint stress had significantly slower tumor growth rates, increased norepinephrine levels, and decreased chemokine (C-C motif) ligand 2 (CCL2) and F4/80 + macrophages, indicating that stress might have reduced the development of melanoma by reducing CCL2 recruitment of tumor-promoting macrophages through norepinephrine (Steinberger et al., 2020) (Fig. 6).This could be associated with the timing of stress exposure, suggesting a nuanced and intriguing connection between stress and tumors.
Stress also directly impacts the metastatic cascade by upregulating signaling pathways associated with migration and invasion.Under stress, GC can affect innate T cell function and reduce the secretion of IL-4 and IFN-γ, weakening their ability to kill tumor cells and inhibit tumor metastasis (Rudak et al., 2021) (Fig. 6).After injection of B16F10 melanoma cells in mice under chronic stress, the more passive experimental groups showed longer immobility duration, shorter travel distance in FST and OFT, and higher levels of lung metastases and corticosterone following the end of the stress period, suggesting that stress might promote tumor development (Goñi-Balentziaga et al., 2020) (Fig. 6).Additionally, norepinephrine can promote angiogenesis and metastasis in melanoma cells by upregulating the expression of VEGF, IL-8, and IL-6 (Yang et al., 2009).Loss of sympathetic and adrenergic tone can upregulate IFN-γ produced by CD8 + T cells in lymph nodes, which might be a mechanism through which the adrenergic system controls the lymph node function (Chen et al., 2021b) (Fig. 6).
Furthermore, stress reduces the efficacy of immunotherapies like checkpoint inhibitors, attributable to GC-mediated inhibition of T cell activity and compromised DC function.Studies have shown that CSDS can lead to anxiety-like behaviors in mice and inhibit the effect of treatment on tumors by affecting the HPA axis to elevate Tsc22d3, which blocks the type I IFN response during DC and IFN-γ T cell activation (Yang et al., 2019).In a CSDS model, stress suppressed the therapeutic effect of a tumor vaccine based on a mouse melanoma model, which might be associated with reduced IFN-γ levels and CD8 + T cell activity (Sommershof et al., 2017).GC can induce selective and tissue-specific expression of the checkpoint molecule, programmed cell death 1 (PD-1), on natural killer (NK) cells, limiting the production of IFN-γ by NK cells in the spleen; this indicates that the body can prevent the development of fatal immunity through the GR-PD1-IFN-γ axis (Quatrini et al., 2018).Furthermore, endogenous GC signaling may regulate CD8 + T cell differentiation in the tumor microenvironment, which is also important for cancer immunotherapy (Acharya et al., 2020).
In addition to melanoma, stress can also affect the development of basal and squamous cell carcinomas by affecting the tumor microenvironment.Chronic stress can suppress the expression of immunerecruiting chemokines like cutaneous T-cell-attracting chemokine/ CCL27, resulting in reduced infiltration of protective T cells and lowered Th1 cytokines (IL-12 and IFN-γ) (Dhabhar et al., 2010).Stress-induced hormonal changes may weaken congenital T cell anticancer abilities, exacerbating cancer development and metastasis (Rudak et al., 2021).Stress has been associated with an increased susceptibility to squamous cell carcinoma by inhibiting type 1 cytokines, protective T cells, and increasing regulatory/suppressor T cell counts (Saul et al., 2005).Stressful events and childhood abuse can lead to worse anti-tumor immune responses and altered mRNA levels of immune-related markers in patients with basal cell carcinoma (Fagundes et al., 2012).

Hair disorders
AA is an autoimmune disease characterized by transient, nonscarring alopecia and preservation of hair follicles.Hair loss can occur in many forms, from well-defined hair loss to diffuse or complete hair loss, with patchy hair loss on the scalp being the most common type (Pratt et al., 2017).AA is caused by lymphocyte infiltration around hair follicles and the increase of IFN-γ.IgG antibodies against hair follicle cells are also present in patients with AA (Simakou et al., 2019).AA is associated with various comorbidities, including depression, anxiety, and autoimmune diseases.In most cases, there is no obvious explanation for AA occurrence; however, multiple triggers, such as bereavement or injury, have been reported (Chu et al., 2011;Villasante Fricke and Miteva, 2015).Studies report that patients with AA have higher rates of stressful life events than controls, suggesting traumatic experiences and psychosocial factors like avoidant attachment and poor social support may contribute to the etiology of AA (Picardi et al., 2003;Willemsen et al., 2009).
A study on the association between stress and hair growth in mice indicated that SP-mediated neurogenic inflammation and NGF might be key regulators of hair growth cessation (Peters et al., 2006).The role of SP in hair growth in mice has been extensively demonstrated (Liu et al., 2013; Wang et al., 2015), and the effect of SP on human hair follicles has also been investigated.Hair follicles respond to SP by premature withdrawal, downregulation of neurokinin-1 (NK1), and upregulation of neutral endopeptidase (SP degradation).This was accompanied by degranulation of MCs in the connective tissue sheath of hair follicles, indicating neurogenic inflammation.A study found that SP could downregulate the immunoreactivity of growth-promoting NGF receptor (TrkA) but upregulate NGF and its apoptosis and catalytic factorpromoting receptor.These results provide a biological explanation for stress-induced telogen effluvium and AA (Peters et al., 2007).CRSinduced acute stress in rats leads to elevated cortisol levels, increased MC count, and upregulated IL-6 and IL-1β, resulting in reduced stimulation of dermal papilla cells and potentially inhibiting hair growth (Shin et al., 2016).
Stress can participate in the process of gray hair and hair loss through the HPA axis and the sympathetic nervous system.It can cause grey hair by activating sympathetic nerves and inducing melanocyte stem cell proliferation and oxidative damage to melanocytes (O'Sullivan et al., 2021;Zhang et al., 2020a).Hair color can also be affected by regulating metabolic pathways and mitochondrial functions under stress (Rosenberg et al., 2021).Chronic stress can also contribute to hair loss by increasing corticosterone levels and affecting the expression of growth arrest-specific 6 in dermal mastoid cells, inhibiting hair follicle stem cell activity (Choi et al., 2021).

Other conditions
Acne is a common skin condition affecting approximately 9.4 % of the global population (Heng and Chew, 2020).Stress is one of the possible factors that can trigger or worsen acne, which can cause physical and psychological distress (Jović et al., 2017).Studies have reported an association between the severity of acne and the level of perceived stress (Misery et al., 2022).International studies have reported that psychological stress is a risk factor for acne (Dreno et al., 2020) and that increased stress can aggravate acne symptoms (Yang et al., 2020).Psychological factors can induce the release of neuropeptides and hormones that activate cells involved in acne (Ganceviciene et al., 2009).Stress leads to increased GC and androgen levels, resulting in increased acne sebum production and increased CRH production and release by dermal nerves and sebum cells; the increase in proinflammatory factors, SP, and lipids may also contribute to the deterioration of acne (Passeron et al., 2021).Furthermore, stress reduces ceramide synthesis, which impairs skin barrier function and increases transepidermal water loss, resulting in dry, irritated, and inflamed skin (Jović et al., 2017).
Vitiligo is a common skin pigmentation disorder characterized by local or generalized depigmented spots, and negative mood due to changes in appearance can lead to aggravation of the lesions or recurrence after recovery (Picardo et al., 2015).Stress triggers vitiligo development (Henning et al., 2020); a study on vitiligo reported that over half of the patients believed that stress was the cause of their illness (Condamina et al., 2022).Psychological stress can increase catecholamines and neuropeptides, affecting melanocyte function through immune responses and oxidative stress, ultimately leading to pigment loss (Henning et al., 2020;Silverberg and Silverberg, 2015).Chen et al. found that mice under CRS had skin surface depigmentation and increased SP expression, and in vitro experiments verified that SP could inhibit the expression of HPA axis-related mediators and melanocortin receptors in skin tissues, indicating that SP is involved in the development of hypopigmentation disorders by binding to NK1 receptor and interfering with melanin metabolism to regulate the HPA axis (Chen et al., 2022).
Lichen planus (LP) is a chronic inflammatory disorder affecting skin and mucous membranes (Liu et al., 2022).The cause of LP is unclear; however, it is classified as an autoimmune disorder that may be triggered or worsened by psychological stress (Kalkur et al., 2015), especially family-related stress (Manolache et al., 2008).Severe psychological stress may also cause LP in healthy individuals (Vicic et al., 2023).Stress may be involved in the pathogenesis of LP by regulating endocrine and immune responses (Krasowska et al., 2008); however, the specific mechanism has not yet been elucidated.
Studies have delineated the relationship between stress and skin diseases; however, more research is needed to elucidate the underlying mechanisms.Understanding how psychological stress impacts the NEI network may shed light on how stress contributes to inflammatory skin diseases.Future studies investigating stress-induced changes in stress hormones, neurotransmitter levels, and immune activity will help clarify mechanisms and identify targets for potential interventions.

Stress and skin treatments
Psychological stress is often overlooked in the treatment of skin diseases; however, it may greatly influence the effect of conventional treatments and patient outcomes.Therefore, assessing patients' mental states and using stress relieving, anti-anxiety, and anti-depressive strategies may be effective approaches to improving patient response.Herein, we provided a brief overview of the current psychiatric approaches to treating skin diseases (Table 3).

Pharmacotherapy
In addition to conventional medications for skin diseases, antidepressants and anxiolytics may also be beneficial by reducing psychological symptoms and physiological inflammation in patients (Beurel et al., 2020).However, the use of such medications in treating skin diseases is still being studied.In a recent study, patients with rosacea using paroxetine, which also improved depressive symptoms, showed a higher rate of response to erythema treatment than the placebo group (Wang et al., 2023).Fluoxetine, a typical selective serotonin reuptake inhibitor, can reduce AD-like symptoms; a study found that fluoxetine significantly reduced anxiety-and depression-like behaviors in mice and decreased MC count in skin tissues and IL-4, IL-13, and IgE levels, indicating that fluoxetine might relieve AD by attenuating the effect of MCs and the Th2-type inflammatory response (Li et al., 2016).A doubleanonymized, randomized controlled trial showed that daily use of 5 % topical doxepin could significantly improve AD symptoms compared with the placebo ointment, indicating that topical doxepin effectively relieves pruritus in patients with AD (Drake et al., 1994).Mirtazapine is effective in treating psoriatic pruritus, AD, and skin malignancies (primary or metastatic); this effect might be associated with the nonhistaminergic induction pathway mediated by the interaction between 5-HT, MC, and nerve endings; however, further experiments are needed to verify this hypothesis (Fawaz et al., 2021).
Currently, research on the mechanisms of pharmacotherapy in treating skin diseases is still limited, particularly regarding their potential modulation of immune and inflammatory responses.Antidepressants and anxiolytics have shown promise in alleviating the symptoms of depression and anxiety and improving the overall quality of life of patients with skin diseases.However, the safety and efficacy of pharmacotherapy have yet to be confirmed through large-scale, multicenter clinical trials.

Cognitive behavioral therapy
In recent years, treatment for skin diseases has shifted from "diseasecentered" to "patient-centered," with cognitive behavioral therapy (CBT) being a relatively representative intervention.Currently, CBT is mainly used for post-traumatic stress, anxiety, obsessive-compulsive disorders, and other systemic diseases such as type 2 diabetes and irritable bowel syndrome (Kim et al., 2022;Matsumoto et al., 2020;Pinhas-Hamiel and Hamiel, 2020;Xian-Yu et al., 2022).Functional magnetic resonance imaging showed that the changes in brain regions might be key to symptom improvement.
CBT can help change problematic patterns of thinking (cognition) and behaviors related to psychological distress through approaches such as relaxation and stress management.CBT can also help patients increase their tolerance to negative thoughts and emotions and reduce their negative disease perception to break the vicious cycle, and patient response to this treatment may be positively correlated with the pretreatment level of itching behavior and serum IgE (Stangier et al., 2004).CBT comprises multiple treatment modules, which utilize different intervention models for different disease features.Studies have reported that treatment for coping behaviors and CBT based on exposure therapy can help relieve symptoms such as itching, depression, and anxiety; reduce steroid use; and improve treatment satisfaction among patients with AD (Hedman-Lagerlöf et al., 2019;Leong et al., 2022).A recent meta-analysis of randomized controlled trials on the relationship between psychological interventions and immune system function revealed that CBT use was significantly associated with better immune functions, which was indicated by lower levels of inflammatory factors, higher immune cell counts, and greater activity of NK cells; the improvement in immune function was maintained through 6 months following treatment discontinuation (Shields et al., 2020).A metaanalysis of 19 studies showed that CBT or mindfulness-based techniques effectively improved the quality of life and anxiety symptoms in patients with psoriasis (Zill et al., 2019).In another study, 40 patients with psoriasis were randomly assigned to receive 8 weeks of CBT with narrow-band ultraviolet B (UVB) phototherapy or 8 weeks of narrowband UVB phototherapy only, and the results showed that the effect of treatment on psoriasis was significantly better in patients receiving phototherapy along with psychotherapy, with 65 % of these patients achieving PASI75, compared with 15 % of patients receiving standard UVB therapy only (Piaserico et al., 2016).Management of patients with vitiligo using interventions such as CBT, mindfulness, acceptance, and commitment therapy can also improve the acceptance, confidence, and self-esteem of the patients, indicating the importance of patientcentered care (Ahmed et al., 2018).
CBT also helps patients manage skin symptoms such as itching, pain, and discomfort.CBT can be delivered by professional mental health experts in different forms, such as traditional, mindfulness-based, or acceptance-based approaches.CBT is usually a long-term treatment that requires regular participation and guidance, and its effectiveness may depend on individual factors, indicating that personalized treatment plans and patient adherence are essential.

Other treatments
Mindfulness therapy is a non-drug psychotherapy that can help treat skin diseases.It involves cultivating attention to and acceptance of the present moment and practicing meditation exercises.It can reduce stress and anxiety and improve the mental health of patients with skin conditions.Studies have shown that mindfulness therapy can improve the skin symptoms and quality of life of patients with AD (Kishimoto et al., 2023;Lüßmann et al., 2021), and it is also effective in patients with psoriasis, acne, and vitiligo (Bartholomew et al., 2022;Rafidi et al., 2022).
Psychological stress can worsen skin diseases and affect patients' quality of life, necessitating the management of the mental health of patients with skin conditions.Mental health interventions, such as psychological support, cognitive behavioral therapy, and stress management, can help patients improve their coping skills, positive mindset, and emotional state.These interventions can help increase the rate of patients' response to dermatological interventions and improve the overall quality of care for these patients.

Conclusion and outlook
Recently, increasing attention has been given to the neuro-immune interaction in skin diseases.Type 2 cytokines can stimulate pruritic sensory neurons through IL-4Rα and Janus kinase-1 signaling, leading to the development of chronic pruritus (Oetjen et al., 2017).In response to the stimulation of allergens, basophils can cause acute pruritus in patients with AD by releasing leukotrienes, which activate the neuroimmune axis (Wang et al., 2021).Furthermore, neuron-restricted IL-33R signaling is a critical regulator causing pruritus when the skin is dry, and IL-33 may be an important therapeutic target for dry skin pruritus and chronic pruritus of unknown cause (Trier et al., 2022).Based on previous studies, endocrine signaling molecules are indispensable for the occurrence and development of skin diseases; external stress also has a certain impact on skin diseases.Therefore, we have summarized the pathogenesis of skin diseases based on the NEI network under stress.
In the present review, we summarized the current studies on the relationship between stress and skin diseases and elaborated on the effects of stress at different levels.We have also discussed how stress impacts the immune system through the HPA axis, sympathetic nervous system, and neuropeptides, affecting skin diseases.The influence of stress on the gut microbiota has been extensively studied recently, with research focusing on patients with skin conditions.Connecting the stress-gut microbiota-skin axis can enhance our understanding of the brain-gut-skin relationship, guiding future research in this direction.Currently, studies have uncovered the phenomenon of central inflammation influencing the periphery through the blood-brain barrier (Kaul et al., 2016;Peng et al., 2022).However, research on how peripheral inflammation affects the central system is limited.Future works may focus on how peripheral inflammatory responses impact the brain by altering the permeability of the blood-brain barrier and causing central inflammation.This is also in line with our goal to understand the brainskin-brain circuit and the interaction between stress and skin diseases observed in clinical settings.
Further knowledge about the stress-related NEI network can improve our understanding of skin diseases and the influence of external factors and provide a new direction for the diagnosis and treatment of skin diseases based on the corresponding mechanisms.The relationship between stress and skin diseases has attracted increasing attention, and new treatments are being investigated and undergoing trials.In-depth studies on the mechanism of skin diseases under stress conditions are still lacking, indicating that the exploration is still at an early stage.A better understanding of the complex relationship between stress and skin diseases can help us find more therapeutic targets in the central or peripheral regions and fundamentally solve the problems related to skin diseases.Hopefully, this could broaden our vision and bring hope to patients with a great burden of skin diseases.

Fig. 4 .
Fig. 4. Effects of stress on skin barrier: Stress increases activity in the amygdala, producing signals of CRF, which activates the anterior pituitary and produces ACTH.The HPA axis ultimately stimulates the adrenal glands to produce GC and EPI, which, along with nerve-derived NE and SP, is involved in the impact on the skin barrier.The above-mentioned stress factors can promote the production of inflammatory factors, such as IL-1, IL-4, IL-5, IL-6, IL-18 and TNF, which promote the skin inflammation and affect skin repair.At the same time, psychological stress can reduce the expression of epidermal antimicrobial peptides, which leads to increased susceptibility to pathogens, increased water loss and increased TEWL; negative emotions will delay wound healing.Neuroendocrine factors may promote the production of cytokines and other effector molecules by interacting with resident cells and immune cells in the skin, eventually leading to skin barrier damage.Abbreviation: CRF, corticotropin releasing factor; ACTH, adrenocorticotropic hormone; HPA, hypothalamic-pituitary-adrenal; GC, glucocorticoid; EPI, epinephrine; NE, noradrenaline; SP, substance P; IL, interleukin; TNF, tumor necrosis factor; TEWL, transepidermal water loss; MC, mast cell; DC, dendritic cell; KC, keratinocyte.

Fig. 5 .
Fig. 5. Neuroendocrine-immune mechanisms linking psychological Stress to skin diseases exacerbation.Psychological stress can aggravate skin diseases through the NEI network, most typically allergic skin diseases and psoriasis.Stress activates the HPA axis, triggering cortisol release from the adrenal gland, and also induces neural signaling leading to neuropeptide secretion.These stress mediators then act on various cell types in the skin.Cortisol and neuropeptides like CRH impair the keratinocyte epidermal barrier and provoke the release of pro-inflammatory cytokines.Neuropeptides also cause MC degranulation, releasing histamine and other inflammatory compounds.Furthermore, cortisol and neuropeptides influence DC, skewing them towards promoting Th2 and Th17 responses implicated in skin inflammation.Stress mediators hinder neutrophil migration, oxidative burst, and NETosis, reducing antimicrobial capacity in the skin.Abbreviation: NEI, neuroendocrine-Immune; HPA, hypothalamic-pituitary-adrenal; CRH, corticotropin releasing hormone; ACTH, Adrenocorticotropic hormone; BDNF, brain-derived neurotrophic factor; MC, mast cell; DC, dendritic cell; VEGF, vascular endothelial growth factor; Th, T helper.

Fig. 6 .
Fig. 6.Impact of stress on skin tumors and their microenvironment.Under stress, the HPA axis and NS are activated and produce EPI, NE, GC, etc., resulting in tumor responses.Stress can change the immune response, reduce the production of effect T cells, NK cells, as well as tumor-inhibiting IFN-γ and IL-4, and increase the number of regulatory T cells and TAMCs.Under stress conditions, circulating tumor cells can also be attracted by macrophages, promoting organ specificity of tumors.Stress also promotes the release of a variety of angiogenesis-promoting factors, such as VEGF and IL-6, on tumors and stromal cells.The stress hormone dopamine can mediate intranuclear HIF-1α by binding to DRD2, thereby participating in the tumor EMT.Abbreviation: HPA, hypothalamic-pituitary-adrenal; NS, nerve system; NE, noradrenaline; EPI, epinephrine; GC, glucocorticoid; NK, natural killer; IFN-γ, interferon gamma; IL, interleukin; TAMC, tumor-associated myeloid cell; VEGF, vascular endothelial growth factor; EMT, epithelial-mesenchymal transition; HIF-1α, hypoxia-inducible factor 1 alpha; DRD2, dopamine receptor D2.