Interleukin-17 in inflammatory skin disorders

PURPOSE OF REVIEW: Recently, a novel and unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from Th1 and Th2 cells, was discovered. The question is addressed as to what extent inflammatory skin diseases are associated with the actions of this newly discovered Th17 cell subset. RECENT FINDINGS: Th17 cells are involved in protection against bacterial pathogens. In addition, it is now clear that Th17 cells may also be crucial in the pathogenesis of various chronic inflammatory diseases that were formerly categorized as Th1-mediated disorders. SUMMARY: In this review, we summarize the current knowledge of IL-17 and Th17 cells and discuss the possible role of IL-17 in the pathology of psoriasis, contact hypersensitivity and atopic dermatitis. Whereas IL-17 may play an important role in the pathogenesis of psoriasis and contact hypersensitivity, its role in atopic dermatitis is still unclear.     

Th22细胞在炎症免疫性疾病中作用的研究进展

Th22细胞是最近发现的CD4+T细胞功能亚群,表达CCR6、CCR4和CCR10,且分泌IL-22和TNF-α,不分泌IFN-γ、IL-4、IL-17,是独立于Th1、Th2和Th17的细胞亚群。Th22细胞主要参与皮肤的自稳调节和病理状态,可以调控皮肤的固有免疫反应、防御功能及表皮损伤后的修复功能,在炎症性皮肤病的病理生理机制中发挥重要作用。此外,Th22细胞也参与了炎症性肠病、类风湿关节炎、肝炎、试验性自身免疫性心肌炎等炎症免疫性疾病的病理过程。本文对Th22细胞其细胞因子IL-22在炎症免疫性疾病中作用的研究进展做一综述。     

Human memory Th17 cells express a functional histamine H4 receptor

The histamine H4 receptor is functionally expressed on CD4(+) T cells and in particular on human CD4(+) Th2-polarized T cells. Interleukin (IL)-17-producing T cells (Th17 cells) represent a newly defined major CD4(+) T-cell subset, having been identified in psoriatic plaques and in acute skin lesions of atopic dermatitis where histamine is also present in high concentrations. To elucidate the role of the histamine H4 receptor (H4R) on these effector T cells, we polarized human memory T cells into Th17 cells. Further, we investigated H4R expression and assessed its function by real-time PCR, by a cytokine secretion assay of IL-17, and by electrophoretic mobility shift assay of activating protein-1 (AP-1). We show that Th17 cells polarized by IL-1β together with IL-23 express the H4R on mRNA and protein level. Additionally, we identified IL-17-positive cells in psoriatic skin lesions. The IL-17-positive lymphocytes were all positive also for functional H4R. Stimulation with histamine or a H4R agonist increased the production of IL-17 and induced activating protein-1 in Th17 cells. In inflammatory skin diseases with enhanced histamine release, such as psoriasis and atopic dermatitis, histamine might foster the immunomodulatory potency of skin-infiltrating Th17 cells.     

IL-17 and IL-22 in atopic allergic disease

A long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role for IL-17-producing (Th17) and IL-22-producing (Th22) T helper cells in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogenesis of allergic diseases. Here we re-evaluate the role of T helper cells, with special focus on the Th17 and Th22 subsets in allergic asthma and atopic dermatitis. Whereas sparse data point to a protective role of the increasing amounts of Th22 cells that are found in chronic stages of both allergies, the data on Th17 cells paint different pictures for the contribution of Th17 cells during subsequent stages of these two forms of allergy.     

Preferential expression of T(h)2-type chemokine and its receptor in atopic dermatitis

Lesional skin of patients with atopic dermatitis (AD) is histologically characterized by hypertrophy of the skin, and the infiltration of a large number of eosinophils and T cells into the dermis. Recent studies have indicated that Th2 cells play a crucial role in the pathogenesis of AD skin. Chemokines and their receptors are implicated in the development of symptoms of various skin diseases such as AD and psoriasis vulgaris (psoriasis). We have examined the in situ expression of a typical Th2-type chemokine, thymus- and activation-regulated chemokine (TARC), and its receptor (CCR4) using immunohistochemical techniques. TARC was found to be highly expressed in the basal epidermis of the lesional skin of AD patients and only slightly in the non-lesional skin. On the other hand, no positive cells were seen in the lesional skin of psoriasis. Consistently, CCR4+ cells were present predominantly in the lesional skin of AD patients, but not in the non-lesional skin. In contrast, in the lesional skin of psoriasis patients, cells positive for CCR5, which is expressed on Th1 cells, were abundantly present. Interestingly, psoralen plus ultraviolet A therapy reduced the number of CCR4+ cells in the AD skin lesions. These results suggest that Th2-type cytokines such as TARC are involved in the pathogenesis of skin lesions in AD patients through the preferential recruitment of Th2 cells.     

The pruritogenic mediator endothelin‐1 shifts the dendritic cell–T‐cell response toward Th17/Th1 polarization

Endothelin‐1 (ET‐1) is associated with skin diseases such as atopic dermatitis (AD) and psoriasis. ET‐1 is enhanced in the skin of patients AD and psoriasis. In addition, plasma levels of ET‐1 are elevated in AD and psoriasis. Although both AD and psoriasis are T‐cell–mediated skin diseases, the association between ET‐1 and the T‐cell immune response has not been clarified. To evaluate the role of ET‐1 in inflammatory skin disease, we sought to investigate the effects of ET‐1 on the functions of dendritic cells (DCs) and subsequent immune responses. For this purpose, we immunohistochemically confirmed the upregulation of ET‐1 in the epidermis of patients with AD or psoriasis. ET‐1 directly induced phenotypic maturation of bone marrow‐derived DCs (BMDCs). In addition, ET‐1 augmented the production of several cytokines and allogeneic stimulatory capacity of BMDCs. Interestingly, ET‐1–activated BMDCs primed T cells to produce Th1 and Th17 cytokines, but not Th2 cytokines. These findings indicate that ET‐1 polarizes the DC–T‐cell response toward Th17/1 differentiation and may augment the persistent course of inflammatory skin diseases.     

Targeting Interleukin-22 in Psoriasis

Interleukin-22 (IL-22) is an IL-10 family cytokine that was recently discovered to be released by T helper 17 (Th17) cells, Th22 cells, etc. Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of psoriasis. For instance, IL-22 can inhibit keratinocyte terminal differentiation and can induce psoriasis-like epidermis alterations; serum IL-22 levels were correlated with the disease severity of psoriasis patients, and IL-22 mRNA was positively expressed in the psoriatic skin lesions, but negatively expressed in the normal controls. All these findings suggest that IL-22 may be implicated in psoriasis; therapeutics targeting IL-22 may have promise as a potential therapeutic target for treating psoriasis. In the present review, we summarize recent advances on the role of IL-22 in the pathogenesis and treatment of psoriasis.     

CD4-CD8- T cells bearing invariant Valpha24JalphaQ TCR alpha-chain are decreased in patients with atopic diseases

Atopic disorders are caused by disregulated activation of T helper 2 (Th2) cells that produce IL-4 and IL-5. Because the presence of IL-4 potently augments the differentiation of naive T cells into Th2 cells, it is important to seek the cell population which provides IL-4 for naive T cells. Recently, a unique subpopulation of T cells, natural killer (NK) T cells, has been shown to produce a large amount of IL-4 upon activation, suggesting their regulatory role in initiation of Th2 cell differentiation. To determine whether NK T cells play a regulatory role in human Th2 cell-mediated atopic diseases, we analysed the frequency of invariant Valpha24JalphaQ CD4-CD8- double-negative (DN) T cells, human NK T cells, in patients with atopic asthma and atopic dermatitis. We also studied cytokine production from Valpha24+ Vbeta11+ DN T cells, which comprise most of Valpha24JalphaQ DN T cells. We found that the invariant Valpha24JalphaQ DN T cells were greatly diminished in patients with asthma and atopic dermatitis. On the other hand, there was no significant difference in Valpha24+ CD4+ T cells possessing invariant Valpha24JalphaQ TCR between healthy subjects and atopic patients. We also found that Valpha24+ Vbeta11+ DN T cells from healthy subjects predominantly produced interferon-gamma (IFN-gamma) but not IL-4 upon activation. These results suggest that NK T cells may not be essential for human atopic disease and that the disappearance of NK T cells, most of which produce IFN-gamma, may be involved in the pathogenesis of atopic diseases.     

The new era for the treatment of psoriasis and psoriatic arthritis: Perspectives and validated strategies

Psoriatic Arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis. Psoriasis (PsO) is a chronic, inflammatory skin disease, characterized by hyperproliferation and aberrant differentiation of keratinocytes. PsA and PsO can be considered as a unique disease and are immune-mediated diseases and both innate and adaptive immunity play a role in their pathogenesis. Initially, PsO and PsA were thought to be Th1-mediated diseases, however, in the last years, several studies have shown the role of interleukin 17 (IL-17) and Th17 cells in the pathogenesis of PsA and PsO. Th17 cells have been detected in dermal infiltrates of psoriatic lesions as well as in synovial fluid. Interleukin (IL)-23, produced by antigen presenting cells (APC), especially by dendritic cells (DC), is the key regulator cytokine for Th17 and IL-17 production. In this review we discuss the role of IL-17 and IL-23 in the pathogenesis of PsO and PsA and their role as therapeutic targets for PsO and PsA treatment.     

Immunobiologics in the treatment of psoriasis

The pathogenesis of various inflammatory cutaneous diseases such as psoriasis, atopic dermatitis and mycosis fungoides relies greatly on the abnormal function of T cells. Fundamental knowledge of the role of T cells in the cutaneous immune response has led to the development and production of biologic molecules designed to block T cell function at various steps, specifically activation (i.e. alefacept, efalizumab), trafficking into inflamed skin (i.e. efalizumab) and effector function under cytokine control (i.e. etanercept, infliximab, adalimumab, and anti-IL-12 antibody). We review the immune abnormalities and the role of T cells in psoriasis, and the recent biologic therapies, which share the common mission to hinder T cell activity in inflammatory diseases. An advantage from the preciseness of these biologic therapies is the potential limit of non-specific and potentially devastating organ toxicity, which commonly plagues other systemic therapies.     

IL-23/IL-17轴在银屑病免疫发病机制中的作用

银屑病是一种以T淋巴细胞异常活化和浸润为主要特征的慢性炎性反应皮肤病。Th17细胞及IL-23/IL-17轴在银屑病的发病机制中可能处于关键地位,并成为新的治疗靶标。IL-23诱导Th17细胞分化增殖,分化成熟的Th17可以分泌IL-17、IL-21、IL-22等多种细胞因子,Th17类细胞因子在银屑病等多种自身免疫疾病和炎性疾病中起重要作用。     

CCL27-transgenic mice show enhanced contact hypersensitivity to Th2, but not Th1 stimuli

CCL27 is one of the CC chemokines produced by epidermal keratinocytes and is suggested to be involved in the pathogenesis of inflammatory skin diseases. To clarify the contribution of CCL27 in skin inflammation, we created transgenic C57BL/6 mice that constitutively produce CCL27 in epidermal keratinocytes. These mice had high serum CCL27 levels and did not show any phenotypical change. Thus we stimulated these mice with various reagents by single and repeated application. Interestingly, only contact hypersensitivity to repeated application with fluorescein isothiocyanate was significantly enhanced in transgenic mice compared to non-transgenic mice. Under this condition, the numbers of inflammatory cells, CCR10-positive cells, CCR4-positive cells and cutaneous lymphocyte-associated antigen-positive cells were increased, and IL-4 mRNA expression was higher in the lesional skin of transgenic mice. Increased number of mast cells and higher serum IgE levels, which were similar to atopic dermatitis, were also observed. These results indicated that CCL27 modified inflammation by attracting CCR10-positive and CCR4-positive cells into the lesional skin, and may participate in the pathogenesis of Th2-shifted skin diseases such as atopic dermatitis.     

CCL17 transgenic mice show an enhanced Th2-type response to both allergic and non-allergic stimuli

CC chemokine ligand (CCL)17 is implicated in the pathogenesis of atopic dermatitis (AD). To study the effect of CCL17 produced by keratinocytes (KC) during inflammation, we created transgenic (Tg) mice in which CCL17 is overexpressed in KC. Th2-type contact hypersensitivity (CHS) was enhanced and Th1-type CHS was suppressed in these mice. Increased numbers of CC chemokine receptor (CCR)4(+) cells and mast cells infiltrated in Tg mice. Levels of IL-4 mRNA were higher and those of IFN-gamma mRNA were lower in both acute and chronic CHS. Higher levels of serum IgE were observed after CHS. Numbers of CCR4(+) cells among PBMC were increased in Tg mice challenged acutely on the trunk. Chronic irritation with croton oil induced dermatitis and an elevation of serum IgE levels. Tg mice showed enhanced ear swelling after tape stripping. CCL17 was thought to modify the inflammation caused by sensitizing reagents as well as irritant reagents by attracting CCR4(+) cells into the lesional skin and creating a Th2-dominant condition. AD-like conditions such as increased number of mast cells and elevated levels of serum IgE were observed. Thus, CCL17 may participate in the pathogenesis of skin diseases such as AD by regulating both allergic and irritant inflammation.     

Role of IL-17 in Psoriasis and Psoriatic Arthritis

The role of T cell subpopulations in human disease is in a transition phase due to continuous discovery of new subsets of T cell, one of which is Th17, characterized by the production of signature cytokine IL-17. In the last couple of years, many articles are coming out on the role of Th17 and its signature cytokine IL-17 in different autoimmune diseases like rheumatoid arthritis, psoriasis, psoriatic arthritis (PsA), SLE and multiple sclerosis. Psoriasis and PsA are immune-mediated diseases, affecting the skin and joints, respectively. Initially, it was thought that psoriasis and PsA were Th1-mediated diseases; however, studies in knockout animal models (IL-17 knockout mice) as well as human experimental data indicate that Th17 and its signature cytokine IL-17 have a critical role in the pathogenesis of psoriatic disease. Th17 cells have been identified from the dermal extracts of psoriatic lesions. Subsequently, our research group has substantiated this observation that Th17 cells are enriched in the papillary dermis of psoriatic plaques and in freshly isolated effector T lymphocytes from the synovial fluid of PsA patients, and we have reported that the majority of these CD4?+?IL-17+ T cells are of memory phenotype (CD4RO⁺CD45RA^?CD11a⁺). Recent reports also suggest that the synovial tissue in psoriatic arthritis is enriched with IL-17R, and its most well recognized receptor IL-17RA is functionally active in psoriatic arthritis. In this review article, we have discussed the role of IL-17 in psoriatic disease and have narrated about the novel IL17/IL-17R antibodies currently in preparation for its therapeutic uses in autoimmune diseases.     

γδ T cells and inflammatory skin diseases

Approximately 25% of the population suffers from skin diseases. The most common forms of skin diseases are the inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis. These diseases are described as T cell–mediated diseases induced by either allergens or autoantigens. Classically, the focus has been on the role of αβ T cells, but it is becoming increasingly clear that γδ T cells play a central role in inflammatory skin diseases. In particular, an important role of IL-17A–producing γδ T cells in these inflammatory skin diseases has been shown in various disease models in mice. Interestingly, various epidermal proteins, which appear to be linked to inflammatory conditions in the skin by yet undescribed mechanisms, are expressed by specific subsets of thymic epithelial cells and mutations in these proteins seem to affect γδ T cell development. The focus of this review is how mutations in epidermal proteins affect γδ T cell development and how γδ T cells, and in particular of IL-17A–producing γδ T cells, contribute to inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis.     

Contrasting pathogenesis of atopic dermatitis and psoriasis--part II: immune cell subsets and therapeutic concepts

Atopic dermatitis (AD) and psoriasis are among the most common inflammatory skin diseases. In the first part of this 2-part review, we discussed the similarities and differences between AD and psoriasis with respect to clinical features and pathology. The diseases are characterized by infiltration of skin lesions by large numbers of inflammatory cells; the second part of this review focuses on immune cell subsets that distinguish each disease and the therapeutic strategies that might be used or developed based on this information. We discuss the interactions among different populations of immune cells that ultimately create the complex inflammatory phenotype of AD and compare these with psoriasis. Therapeutic strategies have been developed for psoriasis based on the cytokine network that promotes inflammation in this disease. Antibodies against IL-12 and IL-23p40 antibody and antagonists of TNF are used to treat patients with psoriasis, and studies are underway to test specific antagonists of IL-23, IL-17, IL-17 receptor, IL-20, and IL-22. We discuss how these therapeutic approaches might be applied to AD.     

Interleukin-21 in autoimmune and inflammatory skin diseases

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases.     

Interleukin-33 alleviates psoriatic inflammation by suppressing the T helper type 17 immune response

Psoriasis is a chronic inflammatory skin disease with unclear pathogenesis. Interleukin-33 (IL-33) is highly expressed in patients with psoriasis, but its role in psoriasis is unknown. The aim of this study was to investigate the possible role of IL-33 in the pathogenesis and treatment of psoriasis. IL-33 expression was determined using enzyme-linked immunosorbent assay, real-time fluorescent quantitative polymerase chain reaction and immunohistochemical staining. CD4⁺ T cells were sorted using magnetic beads and treated with or without IL-33. Imiquimod (IMQ) was used to induce psoriatic inflammation in mice. The frequency of immune cells was determined using flow cytometry. The cytokine level in mouse skin was measured using cytometric bead array. Our results showed that IL-33 was highly expressed in the lesional skin and serum of patients with moderate-to-severe plaque psoriasis. IL-33 inhibited the expression of IL-17 in CD4⁺ T cells of psoriasis patients. Subcutaneous injection of IL-33 alleviated the IMQ-induced psoriatic inflammation in mice, reduced tumor necrosis factor-α and IL-23 expression, and decreased the proportion of T helper type 17 (Th17) cells in the skin-draining lymph nodes in the mice. Our results suggest that IL-33 plays a protective role in the pathogenesis of psoriasis by suppressing Th17 cell differentiation and function. The potential therapeutic effect of IL-33 in treating psoriasis warrants further investigation.     

The CCL20 and CCR6 axis in psoriasis

Psoriasis is a TNF-α/IL-23/IL-17A–mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL-17A–producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL-17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL-17A–rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.     

Cytokine-Based Therapy in Psoriasis

Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2–3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL-17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment.