微生物在痤疮发病中的作用

痤疮是一种累及毛囊皮脂腺的慢性炎症性皮肤疾病。尽管目前痤疮的确切病因及发病机制尚不十分明确,但微生物被认为是其发病的重要病因之一。痤疮丙酸杆菌作为公认的最重要的致病微生物,致病机制主要为诱导炎症反应,促进毛囊皮脂腺上皮角化以及促进皮脂腺分泌等。此外,表皮葡萄球菌、颗粒丙酸杆菌、马拉色菌等亦在痤疮发病中起作用,可与痤疮丙酸杆菌共同致病,主要机制包括激活TLR-2、形成生物膜、脂酶作用等。贪婪丙酸杆菌及另一种新型丙酸杆菌、棒状杆菌、消化道链球菌等可能与痤疮致病相关,但其机制并不明确。不同类型痤疮丙酸杆菌、痤疮丙酸杆菌与痤疮其他致病微生物间可能存在互相抑制作用。     

寻常痤疮的治疗研究进展

寻常痤疮是一种累及毛囊皮脂腺的慢性炎症性皮肤疾病,由多因素综合作用所导致。寻常痤疮的发病主要与雄激素及皮脂增加,毛囊皮脂腺开口处过度角化,痤疮丙酸杆菌感染及继发炎症反应等四大原因相关,目前关于发病机制的研究主要集中于痤疮丙酸杆菌、免疫、游离胰岛素样生长因子-1等因素。治疗上主要以物理疗法、系统药物治疗及局部治疗为主。     

雄激素与痤疮相关研究进展

痤疮是发生在毛囊皮脂腺的慢性炎症性皮肤病,为最常见的损容性皮肤病之一。痤疮由多种病因导致,其发病机制尚未得到完全阐明,通常认为与雄激素水平失衡、毛囊皮脂腺导管角化异常、痤疮丙酸杆菌感染、炎症反应以及遗传等因素有关,其中雄激素在痤疮发病机制中起着重要作用。本文首先介绍雄激素代谢过程,随后围绕其参与痤疮发病机制、与不同人群痤疮患者发病关系及相关治疗作一综述。     

痤疮发病机制及治疗目标的新认识

痤疮丙酸杆菌是寄生在毛囊皮脂腺单位的正常菌群,在痤疮发病中通过天然免疫介导炎症反应,在痤疮亚临床皮损及炎性皮损中持续作用。痤疮不是一种单纯的感染性疾病,炎症反应贯穿痤疮发病过程的始终,甚至包括炎症后红斑、炎症后色素沉着以及瘢痕的形成。基于对痤疮发病机制的重新认识,对于痤疮的治疗也从传统的抗感染治疗向以抗炎治疗为主的转变,该文对其作一综述。     

清痤散面膜联合维胺酯胶囊治疗面部中重度痤疮疗效评价

痤疮是常见的毛囊皮脂腺慢性炎症性疾病,不仅影响美观,还对患者工作生活和社交等产生不良影响[1]。痤疮的发病机制尚未完全清楚,主要与性激素水平、皮脂腺大量分泌、痤疮丙酸杆菌增殖毛囊皮脂腺导管的角化异常及炎症等因素相关[2]。对炎症性痤疮主要治疗药物是维A酸。近来我院采用维胺酯加自制中药面膜治疗炎症性痤疮取得较好效果,现报道如下。     

痤疮的系统性抗菌疗法评价

<正>寻常痤疮发病机制中痤疮丙酸杆菌的定植被认为是痤疮炎症反应形成中重要的因素之一,因此抗生素在痤疮治疗中占有较重要的地位。随着对痤疮丙酸杆菌在痤疮发病中作用更加清晰的理解和越来越多的临床研究显示,系统性抗菌疗法的策略需要改变。1主张抗菌药物每日剂量要减少早期研究认为,活的痤疮丙酸杆菌比死的细菌在诱发痤疮炎症形成中发挥更重要的作用,一旦痤疮丙酸杆菌产生耐药,容易治疗失败。因此在过去指南制定中,强调每日的多西环素或米诺环素剂量     

皮脂腺及皮下脂肪疾病

20101660痤疮丙酸杆菌致病机制研究进展(综述)/汪薇(昆明医学院二附院皮肤科),付萍∥国际皮肤性病学杂志.-2010,36(2).-86~88目前认为痤疮的发病与皮脂分泌过多,毛囊皮脂腺导管开口处角化过度,痤疮丙酸杆菌增殖过度以及炎症反应有关。其中痤疮丙酸杆菌与痤疮的发生有重要关系,在多个致病因素中起核心作用。研究发现,痤疮丙酸杆菌在痤疮发病过程中的各个环节均起重要作用,包括:在粉刺形成中的作用、在痤疮炎症中的作用、在痤疮瘢痕修复过程中的作用。综述痤疮丙酸杆菌在痤疮中的致病机制研究进展,并总结机体对痤疮丙酸杆菌的免疫应答研究进展。认为随着医学研究的不断发展,痤疮丙酸杆菌基因功能的破解、痤     

痤疮与皮肤屏障

痤疮是一种好发于青少年常见的毛囊皮脂腺的慢性炎症性皮肤病,可导致炎症后色素沉着和永久性瘢痕。痤疮的发生发展与皮肤屏障功能有着密切的关系,痤疮发病机制中皮脂分泌增多、毛囊上皮角化过度、致病性痤疮丙酸杆菌定植、炎症反应等因素均会引起皮肤屏障功能损伤,而皮肤屏障功能的损伤加剧了痤疮病情。因此,在治疗痤疮的同时,修复皮肤屏障功能是痤疮防治的重要环节。     

痤疮发病机制的研究进展

痤疮是累及毛囊皮脂腺的慢性炎症性皮肤病,其发病机制复杂,不仅与雄激素介导的皮脂腺分泌增加、皮脂成分改变、毛囊皮脂腺导管角化异常、痤疮丙酸杆菌增殖及炎症反应有关,遗传因素以及饮食习惯也是痤疮发病的重要因素,饮食因素可经胰岛素及IGF-1通过PI3k/Akt信号通路影响痤疮发病,而增强肿瘤坏死因子相关凋亡诱导配体(TRAIL)表达,上调转录因子p53被认为是治疗痤疮的关键。本文综述痤疮各发病机制的最新研究进展,希望能为临床诊治以及科研工作提供新的思路。     

痤疮患者经异维A酸系统治疗后外周血CD14~+单核细胞TLR2的表达变化

目的:探讨Toll样受体2(Toll like receptor 2,TLR2)在寻常痤疮发病中的作用及异维A酸治疗痤疮的部分抗炎机制。方法:应用流式细胞术检测35例痤疮患者经异维A酸治疗前后外周血CD14+单核细胞TLR2的表达,并与对照组25例健康人进行比较。结果:未经治疗的痤疮患者外周血CD14+单核细胞TLR2表达明显高于对照组(t=10.63,P<0.01),治疗后TLR2的表达与对照组无明显差异(t=1.73,P>0.05)。结论:TLR2的表达与痤疮的发病相关;异维A酸治疗后可明显减少外周血CD14+单核细胞TLR2的表达,从而抑制炎症反应的发生。     

Review of the innate immune response in acne vulgaris: activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses

Acne vulgaris is a common disorder that affects 40-50 million people in the USA alone. The pathogenesis of acne is multifactorial, including hormonal, microbiological and immunological mechanisms. One of the factors that contributes to the pathogenesis of acne is Propionibacterium acnes; yet, the molecular mechanism by which P. acnes induces inflammation is not known. Recent studies have demonstrated that microbial agents trigger cytokine responses via Toll-like receptors (TLRs). TLRs are pattern recognition receptors that recognize pathogen-associated molecular patterns conserved among microorganisms and elicit immune responses. We investigated whether TLR2 mediates P. acnes-induced cytokine production in acne. Using transfectant cells we found that TLR2 was sufficient for NF-kappaB activation in response to P. acnes. In addition, peritoneal macrophages from wild-type, TLR6 knockout and TLR1 knockout mice, but not TLR2 knockout mice, produced IL-6 in response to P. acnes.P. acnes induced activation of IL-12 and IL-8 production by primary human monocytes, and this cytokine production was inhibited by anti-TLR2-blocking antibody. Finally, in acne lesions, TLR2 was expressed on the cell surface of macrophages surrounding pilosebaceous follicles. These data suggest that P. acnes triggers inflammatory cytokine responses in acne by activation of TLR2. As such, TLR2 may provide a novel target for the treatment of this common skin disease.     

Glucocorticoids enhance Toll-like receptor 2 expression in human keratinocytes stimulated with Propionibacterium acnes or proinflammatory cytokines

Toll-like receptors (TLRs) on keratinocytes are important cell surface receptors involved in the innate and acquired immune response to invading microorganisms. In acne vulgaris, TLR2 activation by Propionibacterium acnes (P. acnes) may induce skin inflammation via induction of various proinflammatory molecules that stimulate the invasion of inflammatory cells. Although corticosteroids themselves exert immunosuppressive or anti-inflammatory effects, it is well known clinically that systemic or topical glucocorticoid treatment provokes an acneiform reaction. Nevertheless, the effect of steroids on TLR2 expression in human keratinocytes remains unknown. Here, we found that the addition of glucocorticoids, such as dexamethasone and cortisol, to cultured human keratinocytes increased their TLR2 gene expression. Moreover, these glucocorticoids markedly enhanced TLR2 gene expression, which was further stimulated by P. acnes, tumor necrosis factor-alpha, and IL-1alpha. Gene expression of mitogen-activated protein kinase (MAPK) phosphatase-1 was also increased by the addition of dexamethasone. By using several inhibitors and activators, we found that TLR2 gene induction by glucocorticoids was mediated by the suppression of p38 MAPK activity following induction of MAPK phosphatase-1. These findings strongly suggest that steroid-induced TLR2 together with P. acnes existing as normal resident flora plays an important role in the exacerbation of acne vulgaris as well as in possible induction of corticosteroid-induced acne or in that of rosacea-like dermatitis.     

Induction of toll-like receptors by Propionibacterium acnes

BACKGROUND: The bacterium Propionibacterium acnes is involved in the induction and maintenance of the inflammatory phase of acne. Recent studies have found that keratinocytes express toll-like receptors (TLRs) implicated in immediate immunity. No studies have, to date, been carried out on the action of P. acnes upon TLR activation in keratinocytes. OBJECTIVES: Focusing on the inflammatory phase of acne, to clarify the role of P. acnes in immediate immunity by inducing expression of TLR-2 and TLR-4 by keratinocytes. We also studied how the secretion and expression of matrix metalloproteinase (MMP)-9 is induced by P. acnes. METHODS: The work was carried out on two levels: in vivo with the study of the expression of TLR-2 and TLR-4 proteins in biopsies of acne lesions and in vitro on cultured keratinocyte monolayers to study the modulating effects of P. acnes on the expression of TLR-2 and TLR-4 and also on the expression and secretion of MMP-9. RESULTS: Our findings reveal that in vivo TLR-2 and TLR-4 expression is increased in the epidermis of acne lesions. In vitro, an increase in TLR-2 and TLR-4 expression by human keratinocytes occurred in the first hours of incubation with bacterial fractions as well as an increase of the expression and secretion by the keratinocytes of MMP-9, which plays a role in inflammation. CONCLUSIONS: This work demonstrates that P. acnes induces TLR expression and that this mechanism could play an essential role in acne-linked inflammation. These receptors could be involved notably in acute acne.     

All-trans retinoic acid shifts Propionibacterium acnes-induced matrix degradation expression profile toward matrix preservation in human monocytes

Propionibacterium acnes is a critical component in the pathogenesis of acne vulgaris, stimulating the production of various inflammatory mediators, such as cytokines and chemokines, important in the local inflammatory response found in acne. This study explored the role of P. acnes and its ability to induce matrix metalloproteinases (MMPs) in primary human monocytes and how this induction is regulated by retinoids. MMP-1- and MMP-9-expressing cells were present in perifollicular and dermal inflammatory infiltrates within acne lesions, suggesting their role in acne pathogenesis. In vitro, we found that P. acnes induced MMP-9 and MMP-1 mRNA, and the expression of MMP-9, but not of MMP-1, was found to be Toll-like receptor 2-dependent. P. acnes induced the mRNA expression of tissue inhibitors of metalloproteinase (TIMP)-1, the main regulator of MMP-9 and MMP-1. Treatment of monocytes with all-trans retinoic acid (ATRA) significantly decreased baseline MMP-9 expression. Furthermore, co-treatment of monocytes with ATRA and P. acnes inhibited MMP-9 and MMP-1 induction, while augmenting TIMP-1 expression. These data indicate that P. acnes-induced MMPs and TIMPs may be involved in acne pathogenesis and that retinoic acid modulates MMP and TIMP expression, shifting from a matrix-degradative phenotype to a matrix-preserving phenotype.     

Zinc salts inhibit in vitro Toll-like receptor 2 surface expression by keratinocytes

Propionibacterium acnes (P. acnes) plays an important role in the induction and maintenance of the inflammatory phase of acne. At the therapeutic level, it has been shown that zinc salts could have a beneficial effect on mild and moderate inflammatory acne lesions. However, their mechanisms of action are still only partially known. Immediate early immune response is a crucial route in the development of inflammatory reaction and, specifically, activation of Toll-like Receptors (TLRs) leading to nuclear factor (NF)-kappaB translocation and production of inflammatory cytokines such as interleukin-8 (IL-8). The aim of this work was to determine if cytokine secretion and innate immunity could be targets of zinc salts. Normal Human Epidermal Keratinocytes (NHEK) and skin explants were stimulated by P. acnes extracts and incubated (3 h) with zinc salts (1 microg/mL). Then we successively studied TLR2 expression by immunohistochemistry and IL-8 production by ELISA. After incubation with zinc salts, the increase of TLR2 surface expression in skin upon membrane fraction (FM) of P. acnes challenge was decreased as compared to that in control samples. However, this inhibition does not modify IL-8 secretion by keratinocytes. In conclusion the inhibition of TLR2 surface expression by keratinocytes could be one of the anti-inflammatory mechanisms of zinc salts in acne.     

Polyphenon-60 displays a therapeutic effect on acne by suppression of TLR2 and IL-8 expression via down-regulating the ERK1/2 pathway

Propionibacterium acnes (P. acnes) is a well-known acne-inducing factor which causes inflammatory skin lesions by enhancing cytokine production through toll-like receptor 2 (TLR2). Green tea extract catechin has been documented to possess anti-inflammatory effects. However, little is known about the mechanisms involved or any direct effect of green tea catechin on acne. The present study investigated the therapeutic effects and mechanism of polyphenon-60, also known as green tea catechin compound, on acne in vitro and in vivo. In a clinical study using topical polyphenon-60 treatment, acne patients showed symptomatic improvement with decrease in the number of comedos and pustules. To investigate the mechanism underlying the activity of polyphenon-60 in acne therapy, an in vitro study was performed. We found that polyphenon-60 reduced the levels of P. acnes-enhanced TLR2 and interleukin-8 (IL-8) in THP-1 cells, human monocyte cell line and human primary monocytes. Taken together, these data demonstrate that polyphenon-60 has a therapeutic effect on acne by suppressing inflammation, specifically by inhibiting TLR2 expression and IL-8 secretion via down-regulation of extracellular signal-regulated kinases 1/2 (ERK1/2) pathway and activator protein-1 (AP-1) pathway.     

痤疮丙酸杆菌在痤疮发病机制中的进展

痤疮丙酸杆菌在痤疮发病机制中的作用受到越来越多的关注.研究发现,痤疮丙酸杆菌在痤疮患者及健康志愿者皮肤中分布具有菌株差异性,其中痤疮患者主要是Ⅰ型,而健康志愿者主要是Ⅱ、Ⅲ型,痤疮丙酸杆菌的这种菌株差异性在其发病机制中有所体现.不同类型痤疮丙酸杆菌基因具有差异性.其中Ⅰ型缺乏完整的具有防御作用的CRISPR系统,具有某些致病基因特性,其致病能力较Ⅱ型强,Ⅰ、Ⅱ型之间可能存在竞争关系,最终优势菌群的不同在痤疮是否发病中可能占有重要作用,为进一步研究痤疮丙酸杆菌的发病机制及痤疮的诊治带来了新的视角.     

Distinct strains of Propionibacterium acnes induce selective human beta-defensin-2 and interleukin-8 expression in human keratinocytes through toll-like receptors

Acne is a chronic inflammatory disease of the pilosebaceous follicle. One of the main pathogenetic factors in acne is the increased proliferation of Propionibacterium acnes (P. acnes) in the pilosebaceous unit. We investigated whether direct interaction of P. acnes with keratinocytes might be involved in the inflammation and ductal hypercornification in acne. The capacities of different P. acnes strains to activate the innate immune response and the growth of cultured keratinocytes were investigated. We have found that two clinical isolates of P. acnes significantly induced human beta-defensin-2 (hBD2) messenger RNA (mRNA) expression; in contrast a third clinical isolate and the reference strain (ATCC11828) had no effect on hBD2 mRNA expression. In contrast, all four strains significantly induced the interleukin-8 (IL-8) mRNA expression. The P. acnes-induced increase in hBD2 and IL-8 gene expression could be inhibited by anti-Toll-like receptor 2 (TLR2) and anti-TLR4 neutralizing antibodies, suggesting that P. acnes-induced secretion of soluble factors in keratinocytes are both TLR2 and TLR4 dependent. In addition, the clinical isolate P. acnes (889) was capable of inducing keratinocyte cell growth in vitro. Our findings suggest that P. acnes modulates the antimicrobial peptide and chemokine expression of keratinocytes and thereby contributes to the recruitment of inflammatory cells to the sites of infections.     

Toll-like receptor 2 is highly expressed in lesions of acne inversa and colocalizes with C-type lectin receptor

BACKGROUND: Acne inversa (hidradenitis suppurativa) is a chronic inflammatory and cicatricial disorder that affects skin areas rich in apocrine glands and terminal hairs, such as perineum and axillae. The exact pathogenesis of the disease is not well understood and the mechanisms by which bacterial superinfection contributes to the disease progression are not clear. Toll-like receptors (TLRs) expressed by inflammatory cells play a crucial role in the innate immune response to bacteria. OBJECTIVES: We sought to investigate the role of TLR2 in the pathogenesis of acne inversa. METHODS: We investigated the expression of TLR2 using real-time polymerase chain reaction analysis and immunohistochemical stainings of tissue samples from patients with acne inversa. Furthermore, we phenotypically characterized the infiltrating cells and their expression of TLR2. RESULTS: Compared with normal skin, a highly increased in situ expression of TLR2 in acne inversa skin lesions was found at both the mRNA and the protein level. The most abundant cells in the dermal infiltrate of acne inversa were CD68+ macrophages, CD209+ dendritic cells (DCs) and CD3+ T cells. CD19+ B cells and CD56+ natural killer cells were found only in small numbers. Double staining with fluorescence-labelled antibodies showed that TLR2 was expressed by infiltrating macrophages (CD68+) and DCs (CD209+). Flow cytometric analysis of isolated infiltrating cells further confirmed surface expression of TLR2 by macrophages and DCs. CONCLUSIONS: These data indicate that the enhanced expression of TLR2 by infiltrating macrophages and DCs may contribute to the pathogenesis of inflammatory lesions of acne inversa.     

Resolution of inflammatory acne vulgaris may involve regulation of CD4+ T-cell responses to Propionibacterium acnes

BACKGROUND: Propionibacterium acnes has been strongly implicated in inflammatory acne. However, its role in the disease is unclear. It has been hypothesized that an immune response to P. acnes and/or P. acnes heat shock proteins (HSPs) may play a role in the pathogenesis of inflammatory acne. OBJECTIVES: To compare the cell-mediated immune response to P. acnes and HSPs in acne patients, nonacne controls and individuals with resolved acne. METHODS: The proliferative response of peripheral blood mononuclear cells (PBMC) from acne patients, resolved acne donors and healthy controls to P. acnes, P. acnes HSP60 and HSP70, and mycobacterial HSPs was assessed by lymphocyte transformation assay (LTA). The proliferative response of purified CD4+ T cells was further analysed by limiting dilution analysis (LDA). Contingency tables (G-test) were used to analyse the proportion of individuals in each group showing a positive proliferative response for LTA or data fitting single-hit kinetics for LDA. RESULTS: Analysis of stimulation of PBMC with P. acnes, P. acnes HSP60 and HSP70 in the LTA showed the proportion of positive responders to be independent of subject group. However, the proportion of acne patients with a positive response to mycobacterial HSPs was significantly higher than those for the other subject groups. Analysis of LDA data showed the proportion of resolved donors with responses to P. acnes fitting the single-hit kinetics model to be significantly lower than those of the other groups. There were no significant differences in responses to other antigens. CONCLUSIONS: The significantly lower proportion of resolved donors demonstrating a single-hit kinetics response to P. acnes by LDA may represent negative regulation of the CD4+ T-cell response to P. acnes in these subjects.