ABSTRACT
Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.
Subject(s)
Dermatitis, Atopic , Skin Diseases , Humans , Animals , Mice , Prostaglandins , Skin , Fatty AcidsABSTRACT
It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1α (IL-1α) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Dermatitis, Contact/immunology , Skin/immunology , Animals , CD11c Antigen/genetics , Cell Proliferation , Chemokine CXCL2/biosynthesis , Female , Immunologic Memory/immunology , Interleukin-1alpha/pharmacology , Lymphocyte Activation/immunology , Lymphocyte Function-Associated Antigen-1/immunology , Macrophages/cytology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Animal , Neutrophils/immunology , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Skin/pathologyABSTRACT
BACKGROUND: The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping-induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. OBJECTIVE: This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping-induced disruption. METHODS: Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. RESULTS: Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. CONCLUSION: Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury.
Subject(s)
Interleukin-6 , Neuropeptides , Mice , Animals , Interleukin-6/metabolism , Octreotide/metabolism , Epidermis/metabolism , Somatostatin/metabolism , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolismABSTRACT
Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL-2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD-like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.
Subject(s)
Dermatitis, Atopic , Mast Cells , Humans , Immunoglobulin E , Skin/pathology , InflammationABSTRACT
BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown. METHODS: This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel. RESULTS: Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%-8.7%) and 7.2% (95% CI 4.0%-11.5%), respectively. There were significant differences according to cancer type (Gray's test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%-18.0%) at 3 months and 14.2% (95% CI 7.3%-23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%-29.7%) vs 4.3% (95% CI 0.3%-18.2%) at 3 months; and 21.7% (95% CI 7.9%-39.9%) vs 4.3% (95% CI 0.3%-18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64-45.33; Fine-Gray P = .12). CONCLUSIONS: Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Diseases, Interstitial , Lung Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Docetaxel/adverse effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Retrospective Studies , Lung Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/epidemiologyABSTRACT
BACKGROUND: Mast cells (MCs) are tissue-resident cells with various immunologic functions. MCs are increased in atopic dermatitis (AD) skin and can contribute to the inflammation. Although skin MCs are inducible from bone marrow (BM) cells in vitro, they are maintained locally by self-proliferation in the steady state in vivo. However, how skin MCs are increased in AD skin, including the infiltration of BM-derived MC progenitors (MCps) and their differentiation, remains unclear. OBJECTIVE: We sought to identify and characterize BM-derived MCps in AD skin. METHODS: BM-derived MCps in AD skin were analyzed by flow cytometry using BM-chimeric mice and parabiosis in an MC903-induced AD model. BM-derived MCps in AD-like skin were compared with resident MCs for gene expression by RNA- sequencing analysis. RESULTS: We observed local proliferation of resident MCs and an increase in BM-derived MCs in AD-like skin. BM-derived MCs in the skin were derived from circulating MCps and were distinguishable from resident MCs by integrinß7. RNA- sequence analysis showed that integrinß7+ MCs (BM-derived MCps) in the skin shared the characteristics of both mucosal-type MCs and connective tissue-type MCs, and increased the expression of genes related to MCp migration. BM-derived MCps proliferated in situ, gradually lost the integrinß7 expression, and acquired connective tissue-type MC phenotypes during the remission phase of inflammation. CONCLUSIONS: BM-derived integrinß7+ MCps migrate to AD-like skin and contribute to the maintenance of skin MCs.
Subject(s)
Dermatitis, Atopic , Mice , Animals , Dermatitis, Atopic/metabolism , Mast Cells , Bone Marrow/metabolism , Cell Differentiation , Inflammation/metabolism , RNA/metabolismABSTRACT
Activated T cells must mediate effector responses sufficiently to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4(+) T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen-presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs T cell recruitment, transient activation, and rapid desensitization to allow the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host.
Subject(s)
Feedback, Physiological , Inflammation/immunology , Models, Biological , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Animals , Antigen Presentation , Antigens/immunology , Cell Movement , Flow Cytometry , Inflammation/physiopathology , Mice , Mice, Inbred C57BL , Skin/immunologyABSTRACT
BACKGROUND: Psoriasis is a common inflammatory skin disease resulting from dysregulation of the IL-23/TH17 immune axis. The prevalence and severity of psoriasis is higher in men than in women, although the underlying reasons for this are unclear. OBJECTIVE: We studied whether estradiol, a female hormone, plays protective roles in imiquimod-induced psoriatic inflammation in mice by regulating neutrophil and macrophage functions. METHODS: Wild-type mice and conditional knockout mice were ovariectomized, supplemented with placebo or estradiol pellets, and an imiquimod-containing cream applied. RESULTS: Mice without endogenous ovarian hormones exhibited exacerbated psoriatic inflammation including increased production of IL-17A and IL-1ß, which was reversed by exogenously added estradiol. The suppressive effect of estradiol on the production of IL-1ß and IL-17A was abolished in mice lacking estrogen receptors in neutrophils and macrophages (Esr1f/fEsr2f/fLysM-Cre+ mice). IL-1ß, which is required for production of IL-17A in the psoriasis model, was mainly produced by neutrophils and inflammatory macrophages. Estradiol suppressed IL-1ß production from neutrophils and macrophages in mice both in vivo and in vitro and from human neutrophils in vitro. CONCLUSION: Our results suggest a novel mechanism for sex-dependent differences in psoriasis clinical phenotypes that may shed new light on the pathology of psoriasis.
Subject(s)
Interleukin-17 , Psoriasis , Animals , Disease Models, Animal , Estradiol/pharmacology , Estradiol/therapeutic use , Imiquimod/adverse effects , Inflammation/pathology , Interleukin-23 , Macrophages , Mice , Mice, Knockout , Neutrophils , Receptors, Estrogen , SkinABSTRACT
ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12-HEPE as the dominant ω3 fatty acid metabolite in the skin.
Subject(s)
Chemokine CXCL1/metabolism , Dermatitis, Contact/prevention & control , Eicosapentaenoic Acid/analogs & derivatives , Keratinocytes/drug effects , Animals , Antibodies, Monoclonal/drug effects , Antibodies, Monoclonal/metabolism , Bone Marrow Cells , Chemokine CXCL1/genetics , Diet , Dinitrofluorobenzene , Down-Regulation , Eicosapentaenoic Acid/pharmacology , Female , Gene Expression Regulation/drug effects , HaCaT Cells , Humans , Linseed Oil/administration & dosage , Linseed Oil/metabolism , MiceABSTRACT
BACKGROUND: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8+ T-cell-mediated inflammatory skin diseases remains unclear. OBJECTIVE: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8+ T-cell-mediated cutaneous immune responses. METHODS: PD-L1-deficient (Pdl1-/-) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry. RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γ+CD8+ T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis. CONCLUSION: PD-L1 on MCs negatively regulates CD8+ T-cell activation in the skin.
Subject(s)
B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes/immunology , Dermatitis, Contact/immunology , Lymphocyte Activation , Skin/immunology , Animals , B7-H1 Antigen/genetics , CD8-Positive T-Lymphocytes/pathology , Dermatitis, Contact/genetics , Dermatitis, Contact/pathology , Mice , Mice, Knockout , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Skin/pathologyABSTRACT
BACKGROUND: Epidemiologic studies have yielded conflicting results regarding the influence of a single bout of prolonged high-intensity exercise on viral infection. OBJECTIVE: We sought to learn whether prolonged high-intensity exercise either exacerbates or ameliorates herpes simplex virus type 2 (HSV-2) infection according to the interval between virus exposure and exercise. METHODS: Mice were intravaginally infected with HSV-2 and exposed to run on the treadmill. RESULTS: Prolonged high-intensity exercise 17 hours after infection impaired the clearance of HSV-2, while exercise 8 hours after infection enhanced the clearance of HSV-2. These impaired or enhanced immune responses were related to a transient decrease or increase in the number of blood-circulating plasmacytoid dendritic cells. Exercise-induced glucocorticoids transiently decreased the number of circulating plasmacytoid dendritic cells by facilitating their homing to the bone marrow via the CXCL12-CXCR4 axis, which led to their subsequent increase in the blood. CONCLUSION: A single bout of prolonged high-intensity exercise can be either deleterious or beneficial to antiviral immunity.
Subject(s)
Dendritic Cells/immunology , Glucocorticoids/metabolism , Herpes Simplex/immunology , Herpesvirus 2, Human/physiology , Animals , Chemokine CXCL12/metabolism , Exercise , Humans , Immunity , Mice , Mice, Inbred C57BL , Models, Animal , Physical Conditioning, Animal , Receptors, CXCR4/metabolismABSTRACT
BACKGROUND: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.
Subject(s)
Dermatitis, Contact/immunology , Langerhans Cells/immunology , Pituitary Adenylate Cyclase-Activating Polypeptide/immunology , Animals , Denervation , Dermatitis, Contact/genetics , Diterpenes/administration & dosage , Female , Ganglia, Spinal/physiology , Haptens/administration & dosage , Lymph Nodes/immunology , Mice, Inbred BALB C , Mice, Transgenic , Neurotoxins/administration & dosage , Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Receptors, CCR7/immunology , Receptors, CXCR4/immunology , TRPV Cation ChannelsABSTRACT
BACKGROUND: Neutrophilic folliculitis is an inflammatory condition of hair follicles. In some neutrophilic folliculitis, such as in patients with acne and hidradenitis suppurativa, follicular hyperkeratosis is also observed. Neutrophilic folliculitis is often induced and/or exacerbated by a high-fat diet (HFD). However, the molecular mechanisms by which an HFD affects neutrophilic folliculitis are not fully understood. OBJECTIVE: Our aim was to elucidate how an HFD promotes the development of neutrophilic folliculitis. METHODS: Mice were fed an HFD, and their skin was subjected to histologic, RNA sequencing, and imaging mass spectrometry analyses. To examine the effect of an HFD on neutrophil accumulation around the hair follicles, phorbol 12-myristate 13-acetate (PMA) was used as an irritant to the skin. RESULTS: Histologic analysis revealed follicular hyperkeratosis in the skin of HFD-fed mice. RNA sequencing analysis showed that genes related to keratinization, especially in upper hair follicular keratinocytes, were significantly upregulated in HFD-fed mice. Application of PMA to the skin induced neutrophilic folliculitis in HFD-fed mice but not in mice fed a normal diet. Accumulation of neutrophils in the skin and around hair follicles was dependent on CXCR2 signaling, and CXCL1 (a CXCR2 ligand) was produced mainly by hair follicular keratinocytes. Imaging mass spectrometry analysis revealed an increase in fatty acids in the skin of HFD-fed mice. Application of these fatty acids to the skin induced follicular hyperkeratosis and caused PMA-induced neutrophilic folliculitis even in mice fed a normal diet. CONCLUSION: An HFD can facilitate the development of neutrophilic folliculitis with the induction of hyperkeratosis of hair follicles and increased neutrophil infiltration around the hair follicles via CXCR2 signaling.
Subject(s)
Diet, High-Fat/adverse effects , Folliculitis/immunology , Hair Follicle/immunology , Hyperkeratosis, Epidermolytic/immunology , Neutrophil Infiltration/drug effects , Animals , Disease Susceptibility/chemically induced , Disease Susceptibility/immunology , Disease Susceptibility/pathology , Folliculitis/chemically induced , Folliculitis/pathology , Hair Follicle/pathology , Hyperkeratosis, Epidermolytic/chemically induced , Hyperkeratosis, Epidermolytic/pathology , Inflammation/chemically induced , Inflammation/immunology , Inflammation/pathology , Male , MiceABSTRACT
Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.
Subject(s)
Autoimmune Diseases/pathology , Hypohidrosis/pathology , Animals , Autoimmune Diseases/complications , Autoimmune Diseases/immunology , Humans , Hypohidrosis/complications , Hypohidrosis/immunology , Receptor, Muscarinic M3/analysis , Receptor, Muscarinic M3/immunology , Receptors, Cholinergic/analysis , Receptors, Cholinergic/immunology , Urticaria/etiology , Urticaria/immunology , Urticaria/pathologyABSTRACT
Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.
Subject(s)
Alopecia Areata/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dermatitis, Atopic/immunology , Adult , Alopecia Areata/drug therapy , Alopecia Areata/pathology , Antibodies, Monoclonal, Humanized/administration & dosage , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , Cytokines/immunology , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Female , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Male , Middle Aged , Receptors, CCR4/immunology , Receptors, CXCR3/immunology , Young AdultABSTRACT
Atopic dermatitis (AD) is a chronic skin disorder characterized by pruritus and recurrent eczematous lesions that are accompanied by T-helper (Th)2-dominated inflammation. AD Etiology is not yet completely understood, but it is multifactorial. Moreover, the disease is characterized by complex interactions between genetic and environmental factors, such as skin barrier dysfunctions, allergy/immunity, and pruritus. For example, filaggrin is a key protein involved in skin barrier function. Th2 cells produce interleukin (IL)-31, which provokes pruritus, and other Th2 cytokines decrease filaggrin expression by keratinocytes. Dupilumab has recently been developed for AD treatment; its mechanism of action is to bind to IL-4 receptor α and inhibit downstream signaling induced by IL-4 and IL-13. This review summarizes the etiopathogenesis of AD and provides the rationale for selecting a novel targeted therapy.
Subject(s)
Dermatitis, Atopic/etiology , Environment , Gene-Environment Interaction , Genetic Predisposition to Disease , Animals , Anti-Allergic Agents/pharmacology , Anti-Allergic Agents/therapeutic use , Basophils/immunology , Basophils/metabolism , Cytokines/metabolism , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/therapy , Disease Susceptibility , Filaggrin Proteins , Gene Expression Regulation , Humans , Immune System/cytology , Immune System/immunology , Immune System/metabolism , Immunity, Innate , Mast Cells/immunology , Mast Cells/metabolism , Receptors, Antigen, T-Cell, gamma-delta , Skin/immunology , Skin/metabolism , Skin/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolismABSTRACT
Alopecia areata has basically been understood as a type 1 inflammatory disease. Activated NKG2D+ CD8+ cells produce the Th1 cytokine interferon-γ, which leads to the disruption of immune tolerance of hair follicles and the exposure of self-antigens. This results in dense inflammatory cell infiltration and apoptosis around hair follicles, inducing hair loss. A well-known complication of alopecia areata is atopic dermatitis, a typical type 2 inflammatory disease. Hair scientists have shied away from confronting and understanding how alopecia areata, a type 1 inflammatory disease, and atopic dermatitis, a type 2 inflammatory disease, can occur together. This review summarizes the research on the cytokine balance in alopecia areata and then focuses on the classification of the cytokine balance in alopecia areata, including the classification of atopic dermatitis into extrinsic and intrinsic types. Dupilumab reportedly showed dual efficacy in a patient with concomitant atopic dermatitis and alopecia areata, supporting our own experience. Elevated Th2 cytokine levels have also been reported in patients with alopecia areata, with increased serum IL-4, IL-5, IL-6 levels, high IgE levels and elevated eosinophil levels. Because local immunotherapy is a treatment that induces Th2-type inflammation, it may worsen the condition of alopecia areata patients with extrinsic atopic dermatitis. It is desirable to select appropriate treatments with consideration of the cytokine balance.
Subject(s)
Alopecia Areata/immunology , Alopecia Areata/metabolism , Cytokines/metabolism , Dermatitis, Atopic/metabolism , Alopecia Areata/virology , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Chemokines/metabolism , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Dermatologic Agents/therapeutic use , Eosinophils , Humans , Immunoglobulin E/blood , Interleukin-4/blood , Interleukin-5/blood , Interleukin-6/blood , Th2 CellsABSTRACT
BACKGROUND: Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups. METHODS: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC-MS/MS. RESULTS: We show that maternal intake of linseed oil, containing abundant ω3 α-linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14-lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA-derived 14-lipoxygenation products to mouse pups ameliorated their DNFB CHS. CONCLUSION: These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.
Subject(s)
Fatty Acids, Omega-3 , TNF-Related Apoptosis-Inducing Ligand , Animals , Chromatography, Liquid , Dendritic Cells , Fatty Acids, Unsaturated , Mice , Tandem Mass SpectrometryABSTRACT
Lipid mediators, such as prostanoids and leukotrienes (LTs), exert a range of actions through their own receptors on cell surfaces in various pathophysiological conditions. It has been reported that the production of prostanoids and LTs is significantly elevated in the skin lesions of some chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis, showing the possible involvement of these lipid mediators in the development of those diseases. Although the actual significance of these lipid mediators in humans is still unclear, the findings from studies in mice suggest diverse roles of the lipid mediators in the progression or regulation of these diseases. For example, in a mouse AD model, prostaglandin D2 inhibits the induction of Th2 cells through DP receptor on Langerhans cells, while it promotes infiltration of Th2 cells through chemoattractant receptor-homologous molecule expressed on Th2 cells. In a psoriasis model, thromboxane A2-TP signaling promotes psoriatic dermatitis by facilitating IL-17 production from γδ T cells. In this short review, we summarize the current findings on the roles of prostanoids and LTs in AD and psoriasis as revealed by studies in mice, and discuss the potential of these lipid mediators as therapeutic targets in humans.
Subject(s)
Dermatitis, Atopic/immunology , Leukotrienes/immunology , Prostaglandins/immunology , Psoriasis/immunology , Animals , Dermatitis, Atopic/physiopathology , Humans , Psoriasis/physiopathology , Th2 Cells/immunologyABSTRACT
For the induction of adequate cutaneous immune responses, the antigen presentation and recognition that occur in both the skin and skin-draining lymph nodes are essential. In each process of cutaneous immune responses, several distinct subsets of immune cells, including dendritic cells and T cells, are involved, and they elicit their respective functions in a harmonious manner. For example, in the elicitation phase of cutaneous acquired immunity, immune cells form a specific lymphoid structure named inducible skin-associated lymphoid tissue (iSALT) to facilitate efficient antigen presentation in situ. In this short review, we will overview the mechanisms of how antigens are presented and how cutaneous adaptive immune responses are conducted in the skin, especially focusing on contact hypersensitivity, a prototypic adaptive immune response in the skin.