The role of the interleukin-23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis

Alterations in the innate and adaptive immunity underpin psoriasis pathophysiology, with the Th17 cells subset now recognized as the fundamental cells in the key controlling pathway involved in its pathogenesis. Since psoriasis is a systemic disease with important comorbidity, further knowledge on the interleukin (IL)-23/Th17 axis led to the hypothesis that there may be shared pathogenic pathways between primary skin disease and comorbidity. Psoriasis has been identified as a risk factor for cardiovascular and metabolic disease, and increasing evidence gives support to this epidemiological observation from the clinical-pathologically field. As an example, increased levels of IL-23 and IL-23R have been found in human atherosclerotic plaque, and levels correlated with symptom duration and mortality. Also, upregulation of IL-23/IL-17 seems to play an important role in both myocardial damage and stroke, with interesting reports on deleterious effect neutralization after administration of related anti-bodies in both associated conditions. In diabetic patients, increased levels of IL-23/IL-17 have also been observed and available data support a synergistic role of IL-23/IL-17 in β-cells damage. In obesity, signs of an expansion of Th17 subset in adipose tissue have been reported, as well as elevated concentrations of IL-23 in obese patients. In non-alcoholic fatty liver disease, closely related to metabolic syndrome, but also in other mentioned cardiometabolic disorders, a predominance of IL-23 and other related pro-inflammatory factors has been identified as participating in their pathogenesis. Thus, the involvement of the IL-23/Th17 axis in these shared psoriasis-cardiometabolic pathogenic mechanisms is reviewed and discussed in the light of the existing preclinical and clinical evidence, including that from comorbid psoriasis patients.     

The roles of cells and cytokines in the pathogenesis of psoriasis

Psoriasis is considered an immune chronic disease in which T cells are accepted as important. Nowadays, it is believed that psoriasis is most likely a T helper (Th)1/Th17 induced inflammatory disease. However, some other cells, such as endothelial cells, dendritic cells, monocytic cells, neutrophils, keratinocytes, and several cytokines, appear to have, at different stages of the disease, an important role in its pathogenesis. For instance, the response to psoriasis therapy is dependent not only on the inactivation of Th1 and Th17 immune responses but also on the inactivation of dendritic cell products. Moreover, interleukin (IL)-23 deregulation appears to be an independent factor in the pathogenesis of psoriasis. Indeed, currently, the IL-23/Th17 axis is believed to be crucial in psoriasis pathogenesis, and its inhibition appears to be important for therapeutic achievement. This review presents the roles and interactions of cells and cytokines that are related to psoriasis pathogenesis.     

T helper type 17 in psoriasis: From basic immunology to clinical practice

Psoriasis is a chronic inflammatory disease mediated by a complex interplay between immune system and keratinocytes. Initially considered as a keratinocyte proliferation/differentiation disorder, an immune dysregulation was confirmed after the successful treatment of psoriasis with cyclosporine. The ying–yang theory, or T helper type 1 (Th1)/Th2 concept, was then introduced to explain the rarity of atopic dermatitis in patients with psoriasis and the aggravation of psoriasis after interferon-γ treatment. However, recent advances have revised the Th1/Th2 paradigm after the discovery of a novel subset of T cells, called Th17 cells. Th17 cells produce interleukin (IL)-17 and IL-22, and have other important downstream proinflammatory effects on skin, leading to clinical and pathological features typical of psoriasis. Nowadays, emerging evidence suggests integrative and complicated inflammatory circuits among Th1 and Th17 cells and keratinocytes in the pathogenesis of psoriasis, with Th17 cells playing a central role. Herein, we review the biology of Th17 cells as well as the reciprocal interplay between Th17 and regulatory T cells in psoriasis. Integration of the IL-23/Th17 axis into a revised concept of psoriasis has already been translated into novel therapeutic strategies. Studies investigating the effect and molecular mechanism of conventional and biological therapy for psoriasis on the IL-23/Th17 pathway were also discussed.     

生物制剂治疗银屑病的药物遗传学研究进展

研究者们发现IL-23/Th7轴在银屑病发病中具有中心地位,直接或间接靶向于此通路的生物制剂如TNF-α抑制剂、IL-12/23抑制剂、IL-17抑制剂等在治疗中重度银屑病中有明显疗效。药物遗传学通过研究药物疗效与不同个体之间基因多态性的关联,可以预测药物疗效的个体差异。生物制剂的药物遗传学研究和应用可以使银屑病的治疗更加合理及个体化,本文对生物制剂治疗银屑病的药物遗传学研究进行了综述。     

调节性T淋巴细胞和Th17细胞与银屑病的研究进展

银屑病是一种与T淋巴细胞相关的自身免疫性疾病,新近研究发现,除了与Th1细胞有关外,调节性T淋巴细胞尤其叉头/翅膀状螺旋转录因子诱导表达的调节性T细胞和Th17细胞在银屑病的发病过程中起着非常重要的作用。其中,叉头/翅膀状螺旋转录因子（＋）调节性T细胞平衡免疫抑制和免疫激活的转换在银屑病加重方面起到关键作用,Th17细胞分泌的细胞因子IL-17A、IL-17F、IL-22、IL-23、IL-36及肿瘤坏死因子α等在皮肤疾病发生发展中起到重要的作用。银屑病是由调节性T细胞和Th17细胞等多种免疫细胞和细胞因子共同参与的疾病。     

银屑病性关节炎患者Th17/Treg相关细胞因子的检测

目的探讨Th17/Treg细胞相关细胞因子IL-17,IL-6,IL-23和TGF-β在银屑病性关节炎(PsA)发病机制中的作用。方法采用酶联免疫吸附法(ELISA)测定31例PsA患者和30例正常对照者血清中IL-17,IL-6,IL-23和TGF-β的水平。结果 PsA患者血清中IL-17,IL-6和IL-23水平明显高于健康对照组,TGF-β的水平低于健康对照组,差异均有统计学意义(P均<0.05)。结论外周血中Th17/Treg细胞相关的细胞因子IL-17,IL-6,IL-23和TGF-β表达异常参与了PsA的发病过程。     

Comparison of Th1 and Th17 Inflammatory Cytokine Profiles Between Chronic Plaque and Acute Guttate Psoriasis

BackgroundThe phenotypic heterogeneity of psoriasis is suspected to reflect differences in its pathogenesis, but not yet completely elucidated. Studies of the Th1 and Th17 cytokines associated with different phenotypes of psoriasis have yielded inconsistent results.ObjectiveTo investigate the tissue expression levels of Th1 and Th17 cytokines among patients with chronic plaque psoriasis, acute guttate psoriasis, and healthy control.MethodsA total of 20 patients with psoriasis (10 with chronic plaque type and 10 with acute guttate type) and 5 healthy controls were enrolled. The tissue mRNA and protein levels of following cytokines were measured: interleukin (IL)-12, IL-2, interferon (IFN)-γ, IL-23, IL-17A, and IL-22.ResultsThe tissue mRNA levels of IL-12, IFN-γ, IL-23, IL-17A, IL-22 and the protein levels of IL-12, IL-2, IFN-γ, IL-17A, IL-22 were significantly increased in the psoriasis patients compared with the healthy controls. In comparisons of the subtypes, the tissue mRNA level of IFN-γ was increased in acute guttate psoriasis, whereas the protein levels of IL-12 and IL-17A were significantly increased in chronic plaque psoriasis. The cytokine ratios of IL-17A/IL-2 and IL-22/IL-2 were significantly higher in chronic plaque psoriasis than in acute guttate psoriasis.ConclusionWe confirmed that the tissue levels of Th1 and Th17 cytokines were increased in psoriasis patients compared with healthy controls. The increased IFN-γ mRNA level in acute guttate psoriasis and increased IL-12 and IL-17A protein levels in chronic plaque psoriasis suggest that an imbalance between Th1 and Th17 cytokines may play a role in the phenotypic transition of psoriasis.     

生物制剂治疗泛发性脓疱型银屑病的研究进展

泛发性脓疱型银屑病(GPP)的治疗较为困难。近年来的研究表明,TNF-α、IL-17、IL-1、IL-36、IL-12/23在GPP的发病机制中均起着重要作用,可以作为GPP的特异性免疫治疗靶点。针对这些靶点的新型生物制剂如TNF-α抑制剂、IL-17抑制剂、IL-1受体拮抗剂、IL-36受体拮抗剂以及IL-12/23拮抗剂的使用,可以有效治疗该病。本文就近年来相关临床研究文献展开综述,为GPP的临床治疗提供新的思路。     

Role of IL-17 and IL-22 in autoimmunity and cancer

The dysregulation of inflammatory cytokines can cause a variety of diseases, such as autoimmunity and cancer. Since their identification in 2005, Th17 cells and its signature cytokine IL-17, have been implicated in the pathogenesis of autoimmune diseases such as psoriasis and rheumatoid arthritis (RA), and inflammatory associated cancers such as colorectal carcinoma (CRC). Recently, IL-22 a Th17 related cytokine has been shown to be pathogenic in psoriasis and RA. In this review, we will summarize the biological functions of IL-17 and IL-22, their role in autoimmune diseases and briefly review results from clinical trials targeting IL-17 or its receptor for the treatment of autoimmune diseases. Next, we will discuss pre-clinical and clinical data supporting the rationale of targeting other cytokines implicated in the Th17/IL-17 pathway, such as IL-22 and IL-23. Finally, we discuss the role of IL-17, and in particularly IL-22 in tumour immunity and possible therapeutic interventions.     

白细胞介素17A介导银屑病及心血管合并症的研究进展

白细胞介素（IL）-23/IL-17轴是寻常型斑块状银屑病发病的主要通路,IL-17A是相关免疫通路中的关键节点,介导了动脉粥样硬化和银屑病的重叠炎症通路,促进炎症、凝血和血栓形成,在银屑病心血管合并症的发生发展中起重要作用。抑制IL-17A的炎症作用能减少重度银屑病患者心血管合并症的发生率及病死率。本文综述近年来IL...     

Development of psoriasis by continuous neutrophil infiltration into the epidermis

Remarkable effects of anti‐IL‐17A and anti‐IL‐23 antibodies on psoriasis indicate deep involvement of IL‐23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen‐presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, “detachment‐mediated cell proliferation.” This passing is continuously repeated and leads to elongation of rete ridges. The IL‐23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL‐17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL‐23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL‐23 and IL‐1β. In this manner, the framework of the IL‐23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL‐17A production by neutrophils and ending in IL‐17A production by nTh17 cells. Therapeutic mechanisms of anti‐IL‐17A and anti‐IL‐23 antibodies, targeting neutrophils, were also described.     

Dendritic cells: The driver of psoriasis

Psoriasis is a chronic skin inflammatory disorder, the immune mechanism of which has been profoundly elucidated in the past few years. The dominance of the interleukin (IL)-23/IL-17 axis is a significant breakthrough in the understanding of the pathogenesis of psoriasis, and treatment targeting IL-23 and IL-17 has successfully benefited patients with the disease. The skin contains a complex network of dendritic cells (DC) mainly composed of epidermal Langerhans cells, bone marrow-derived dermal conventional DC, plasmacytoid DC and inflammatory DC. As the prominent cellular source of α-interferon, tumor necrosis factor-α, IL-12 and IL-23, DC play a pivotal role in psoriasis. Thus, targeting pathogenic DC subsets is a valid strategy for alleviating and preventing psoriasis and other DC-derived diseases. In this review, we survey the known role of DC in this disease.     

Pathogenic role of IL-17 in psoriasis and psoriatic arthritis

Psoriasis is a chronic inflammatory skin disorder resulting from a complex network of cytokines and chemokines produced by various immune cell types and tissue cells. Emerging evidence suggests a central role of IL-17 and IL-23/T17 axis in the pathogenesis of psoriasis, giving a rationale for using IL-17-blocking agents as therapeutics.Three agents targeting IL-17 signaling are being studied in Phase III clinical trials: secukinumab and ixekizumab (IL-17 neutralizing agents), and brodalumab (IL-17 receptor antagonist). Preliminary results are highly promising for all anti-IL17 agents, creating fair expectations on this class of agents as the new effective therapeutic approach for the treatment of psoriasis.     

Suppression of neuropeptide by botulinum toxin improves imiquimod-induced psoriasis-like dermatitis via the regulation of neuroimmune system

BackgroundPsoriasis is a multifactorial disease arises from a complex interaction of genetics, immune system, and environmental aspects. IL-23/Th17 immune axis has been considered as a primary modulator in psoriasis. In addition, several findings imply that nervous system may take a part in the pathogenesis of psoriasis, suggesting that nervous system, through its neuropeptide, may interact with immune system and lead to the formation of psoriasis.ObjectiveWe aimed to ascertain the role of neuropeptides secreted from neurons in the pathogenesis of psoriasis in vivo.MethodsThe release of neuropeptide was inhibited by injecting Botulinum toxin B (BTX-B) on Imiquimod (IMQ)-induced psoriasis-like dermatitis mice model. Quantification of skin dermatitis, infiltrating inflammatory cells, and the production of cytokines at the lesional skin area were performed by PSI score, immunostaining, and real-time PCR. We also tested the effect of selective CGRP antagonist (CGRP_8?37) on psoriasis-like dermatitis in IMQ-treated mice.ResultsBTX-B injection significantly suppressed PSI score and reduced the number of CD4⁺ T cells, CD11c⁺ dendritic cells, and the production of IL-17A/F in the lesional skin. The expressions of PGP9.5⁺ nerve fibers and neuropeptides (SP, CGRP) were also significantly reduced following BTX-B injection. Additionally, CGRP antagonist also suppressed the development of IMQ-induced psoriasis-like dermatitis in mice.ConclusionThe suppression of neuropeptide secretion in the skin by BTX injection might inhibit nerve elongation, the infiltration of immune cells, as well as IL-17 production, resulting in the improvement of psoriasis. Neuropeptide inhibitor could also be applied to the treatment of psoriasis.     

白细胞介素17A在银屑病发病及治疗中的研究进展

【摘要】 近十余年来的基础和临床研究发现并确立了Th17/白细胞介素17A（IL-17A）在银屑病发病中的核心地位。IL-17A不仅能影响角质形成细胞的增殖活性和细胞功能,对银屑病免疫病理环境中的免疫细胞和相关细胞因子也有很重要的调控作用。近年来针对IL-17A通路的单抗如司库奇尤单抗、ixekizumab、brodalumab等在国内外陆续上市,在临床应用中展现出了显著的疗效。本文介绍IL-17A在银屑病发病机制中的作用以及靶向IL-17A及其受体IL-17RA生物治疗的最新进展。     

IL-17 and its role in inflammatory,autoimmune, and oncological skin diseases: state of art

Recent data support the theory of the involvement of IL-17 in the pathogenesis of several chronic inflammatory skin diseases (psoriasis, atopic dermatitis, acne, hidradenitis suppurativa) and autoimmune skin diseases (alopecia areata, vitiligo, bullous diseases). Even if the role of IL-17 in inflammatory and autoimmune diseases has been reported extensively, its role in tumor is still controversial. Some reports show that Th17 cells eradicate tumors, while others reveal that they promote the initiation and early growth of tumors. Herein, we review the role of IL-17 in the involvement of some common dermatologic diseases: psoriasis, atopic dermatitis, hidradenitis suppurativa, acne, vitiligo, melanoma, and nonmelanoma skin cancers.     

IL-23-mediated epidermal hyperplasia is dependent on IL-6

Psoriasis is a chronic inflammatory skin disease primarily driven by Th17 cells. IL-23 facilitates the differentiation and induces complete maturation of Th17 cells. Lesional psoriatic skin has increased levels of IL-23 and recent studies show that intradermal injections of IL-23 induce a psoriasis-like skin phenotype in mice. We have now characterized the IL-23-induced skin inflammation in mice at the molecular level and found a significant correlation with the gene expression profile from lesional psoriatic skin. As observed in psoriasis, the pathogenesis of the IL-23-induced skin inflammation in mice is driven by Th17 cells. We demonstrate a dramatic upregulation of IL-6 mRNA and protein after intradermal injections of IL-23 in mice. Using IL-6(-/-) mice we show that IL-6 is essential for development of the IL-23-elicited responses. Despite producing high levels of IL-22, IL-6(-/-) mice were unable to express the high-affinity IL-22 receptor chain and produced minimal IL-17A in response to intradermal injections of IL-23. In conclusion, we provide evidence for the critical role played by IL-6 in IL-23-induced skin inflammation and show that IL-6 is required for expression of IL-22R1A.     

白芍总苷对轻、中度寻常性银屑病患者血清中IL-17和IL-23的影响

目的通过检测白芍总苷(TGP)治疗前后寻常性银屑病(PV)患者血清中Th17细胞的相关细胞因子IL~17和IL-23水平,探讨TGP治疗寻常性银屑病的可能作用机制。方法采用双抗体夹心酶联免疫吸附法(ELISA)检测30例PV患者经TGP治疗前后及20例健康对照组外周血清中IL-17和IL-23水平的改变,并分析这两种炎症因子在治疗前、后与PASI评分的相关性。结果治疗前PV患者血清IL-17和IL-23水平均较健康对照组显著升高(P<0.05);TGP治疗后血清中IL-17和IL-23水平均较治疗前显著降低(P<0.05);治疗前、后患者血清IL-17和IL-23水平与PASI评分均呈正相关(P均<0.05)。结论 TGP可能通过调节Th17细胞相关细胞因子IL-17和IL-23发挥治疗银屑病的作用。     

银屑病基因-基因交互作用研究进展

全基因组关联研究发现,对基因-基因交互作用在银屑病发病中的研究取得了积极进展,增进了对银屑病遗传学发病机制的认识。目前,银屑病基因-基因交互作用主要集中在主要组织相容性复合体易感区域和IL23／Thl7信号通路。主要组织相容性复合体区域是最早被发现而且是银屑病发病机制中最重要的易感区域。研究表明,其与内质网氨基肽酶1（ERAPl）基因、抑半胱氨酸蛋白酶蛋白A（CSTA）基因、LCE基因簇及染色体19p13区域（PSORS6）等存在相互作用。白介素23／Thl7是一个与慢性炎症性疾病发病密切相关的重要通路,研究发现其中的多个基因在银屑病发病中存在交互作用。