Wen Hao Wu

Association of Stress with Symptoms of Atopic Dermatitis

Psychological stress and atopic dermatitis (AD) symptoms appear to form a vicious cycle. This study compared the degree of stress and impairment of dermatology life quality between patients with AD and healthy controls, and examined for neuropeptides and neurotrophins associated with stress in AD. Questionnaires, comprising five tests evaluating depression, anxiety, interaction anxiousness, private body consciousness, and dermatology life quality, were examined in age- and sex-matched patients with AD (n = 28) and healthy controls (n = 28). Immunohistochemical staining of nerve growth factor, substance P, corticotrophin-releasing factor receptor and neuropeptide Y was performed in the AD-involved and normal skin. Patients with AD showed high scores on all of the questionnaires, including Beck Depression Inventory, state anxiety, trait anxiety, Interaction Anxiousness Scale, Private Body Consciousness subscale, and Dermatology Life Quality Index. All of the parameters, except for Beck Depression Inventory, showed higher values in AD than healthy controls (p < 0.001). Statistically significant correlations were observed between each psychological parameter and Dermatology Life Quality Index. Among the clinical parameters, only pruritus was positively correlated with state anxiety (R = 0.573, p < 0.05) and trait anxiety (R = 0.525, p < 0.05). The Eczema Area and Severity Index score did not show any significant correlations with psychological parameters. Nerve growth factor-reactive cells were observed more abundantly and intensely in both epidermis and dermis of AD involved skin (n = 4) than in healthy controls (n = 3) (p = 0.022 and 0.029, respectively). Also, the number and intensity of neuropeptide Y-positive cells was significantly greater in the entire epidermis of patients with AD than in healthy controls (n = 3) (p = 0.029 and 0.026, respectively). We conclude that anxiety may be associated with the induction of pruritus through neuro-peptide Y and nerve growth factor.

Thymic stromal lymphopoietin–activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis

BACKGROUND Although invariant natural killer T (iNKT) cells have been shown to play a critical role in the pathogenesis of asthma, the role of iNKT cells in atopic dermatitis (AD) has not been well evaluated. OBJECTIVE We investigated whether iNKT cells in patients with AD increased and whether iNKT cells were activated by thymic stromal lymphopoietin (TSLP), which is highly expressed in keratinocytes of AD. METHODS We assessed the population of iNKT cells in PBMCs of patients with AD and healthy controls (HCs) using flow cytometry. Immunohistochemistry was used to evaluate iNKT cells and TSLP expression in AD and HC skin. We also evaluated whether iNKT cells expressed the TSLP receptor, the effects of TSLP on iNKT cells, and iNKT cell-dendritic cell interactions in a TSLP-rich environment. RESULTS There were more iNKT cells among PBMCs of patients with moderate to severe AD than mild AD (P < .05) and HC (P < .001). The number of iNKT cells was significantly larger in severe AD skin lesions than in mild (P < .001) or moderate AD skin lesions (P < .05). TSLP expression increased in lesional skin (P < .001) but not in the sera of patients with AD (P = .729) compared with HC. iNKT cells expressed TSLP receptor protein and mRNA. TSLP directly activated iNKT cells to secrete IL-4 and IL-13, and the concurrent addition of dendritic cells further activated IFN-gamma expression. CONCLUSION Increased iNKT cells activated by TSLP, especially in patients with severe AD, might play an essential role in the innate allergic immune response in AD.

Corticotropin-releasing hormone downregulates IL-10 production by adaptive forkhead box protein 3–negative regulatory T cells in patients with atopic dermatitis

BACKGROUND Corticotropin-releasing hormone (CRH) is the central regulating hormone of the hypothalamic-pituitary-adrenal axis. CRH also has diverse functional effects in the periphery and is related to the aggravation of several cutaneous diseases; however, the effect of CRH on T cells in patients with atopic dermatitis (AD) has not been well evaluated. OBJECTIVE We investigated whether CRH directly affects peripheral T(H)1, T(H)2, and regulatory T (Treg) cells in patients with AD. METHODS We assessed whether T cells express the CRH receptor protein and mRNA by using flow cytometry, Western blotting, immunofluorescence, immunohistochemistry, and RT-PCR. We evaluated cytokine expression using ELISA after treating the T cells extracted from patients with AD and healthy control subjects (HCs) with CRH. Flow cytometry was then used to evaluate any direct effects of CRH on T(H)1, T(H)2, and Treg cells from patients with AD and HCs. RESULTS T cells from patients with AD expressed significantly lower CRH receptor 1/2 mRNA levels than T cells from HCs. T cells from HCs reacted with different IL-4 and IFN-γ secretions to CRH treatment, whereas T cells from patients with AD did not. IL-10 production was significantly decreased in the supernatants from both the HCs and patients with AD after CRH treatment. CRH upregulated IL-4 production by T(H)2 cells and downregulated IFN-γ production by T(H)1 cells in HCs. CRH also suppressed the production of IL-10 by forkhead box protein 3-negative Treg cells in both groups, but the difference was only significant in patients with AD. CONCLUSIONS CRH-mediated suppression of IL-10 secretion from Treg cells might explain stress-related exacerbations in patients with AD.

CC chemokines as potential immunologic markers correlated with clinical improvement of atopic dermatitis patients by immunotherapy

Please cite this paper as: CC chemokines as potential immunologic markers correlated with clinical improvement of atopic dermatitis patients by immunotherapy. Experimental Dermatology 2010; 19: 246–251.

Increased expression of CC chemokine ligand 18 in extrinsic atopic dermatitis patients.

Background:  Although most patients with atopic dermatitis (AD) show high total and allergen‐specific serum immunoglobulin E (IgE) levels, a small subgroup of AD patients have normal total IgE levels and negative serum allergen‐specific IgE. This subgroup has been termed ‘intrinsic’ AD (IAD) as a counterpart to ‘extrinsic’ AD (EAD). However, the difference of chemokines between IAD and EAD has not yet been evaluated.

Corticotropin‐releasing factor decreases IL‐18 in the monocyte‐derived dendritic cell

Abstract:  Recent evidence suggests that crosstalk between mast cells, nerves and keratinocytes might be involved in the exacerbation of inflammatory conditions by stress, but the mechanism by which this occurs remains unclear. Corticotropin‐releasing factor (CRF), which activates the hypothalamo‐pituitary‐adrenal (HPA) axis under stress, also has pro‐inflammatory peripheral effects. However, there have been no reports about CRF receptor expression and the functional role of CRF in the dendritic cell (DC), which is considered to be the link between allergen uptake and the clinical manifestations of allergic diseases, such as atopic dermatitis. The purpose of this study was to investigate the expression of CRF receptors and the functional role of CRF in the monocyte‐derived DC (MoDC) of atopic dermatitis patients and non‐atopic healthy controls. In this study, mRNAs for CRF‐R1α and 1β, as well as the CRF‐R1 protein, were detected in MoDCs. CRF‐R2α (but not R2β or R2γ) mRNA and the CRF‐R2 protein were present in MoDCs. Exposure of DCs to CRF resulted in a decrease of IL‐18 in both atopic dermatitis patients and non‐atopic healthy controls. However, CRF did not alter the expression of IL‐6, CCL17, CCL18, and CCL22. Therefore, our results demonstrate that CRF could modulate immune responses by acting directly upon DCs.

Statins inhibit chemotactic interaction between CCL20 and CCR6 in vitro: possible relevance to psoriasis treatment

Abstract:  Psoriasis is a chronic IL‐23/Th17 pathway‐associated skin disease. An increased expression of lesional CCL20 can recruit CCR6+ Th17, and lesional cytokine milieu persistently activates keratinocytes to produce CCL20. Lipid‐lowering drugs, statins, are known to possess immune‐modulating functions. In this study, we explored an inhibitory effect of statins on CCL20/CCR6 interaction. We demonstrated that IL‐1β, TNF‐α, and IL‐17A significantly increased CCL20 production from HaCaT cells. However, these increments were markedly inhibited by fluvastatin and simvastatin, but not by pravastatin. In the chemotaxis migration assay, pretreatment with fluvastatin and simvastatin inhibited the migration of human CD4+ T cells towards CCL20. However, the level of CCR6 surface expression in memory CD4+ T cells was not affected. Our results suggest that not all, but specific types of statins may be of benefit in alleviating psoriasis partially via interrupting CCL20/CCR6 chemotactic interaction, the mechanism which may eventually lessen the infiltration of Th17 cells.

Attenuation of contact hypersensitivity by cell-permeable heat shock protein 70 in BALB/c mouse model.

In contact hypersensitivity (CHS), multiple cells, inflammatory mediators and cytokines are known to be involved in the regulation of the immune response. Previously, we revealed the reactive oxygen species generation by 2, 4, 6‐trinitrobenzene sulphonic acid (TNBS) in vivo, followed by heat shock protein 70 (Hsp70) carbonylation and the exogenous antioxidant role of cell‐permeable Hsp70. Here, we demonstrate the role of Hsp70 using cell‐permeable Hsp70 in the mouse CHS model. Pretreatment of cell‐permeable Hsp70: (i) suppressed ear swelling; (ii) down‐regulated phosphorylated p38, but up‐regulated phosphorylated extracellular signal‐regulated kinase; (iii) increased population of CD4+CD25+Foxp3+ T cells; (iv) decreased secretion of tumor necrosis factor‐α (TNF‐α), IL‐12, interferon‐γ and IL‐2 and (v) but up‐regulated IL‐4 and transforming growth factor beta (TGF‐β) in the lymph nodes. In conclusion, cell‐permeable Hsp70 attenuates CHS through modulation of MAPK pathway and regulation of Th1, Th2 and regulatory T cells.