The pathogenesis of acne

Acne vulgaris is a multifactorial disease of as yet incompletely elucidated etiology and pathogenesis. The following have been identified as the most significant factors: follicular hyperkeratosis, increased sebum secretion, Propionibacterium (P.) acnes, and inflammation. Increased sebum production and follicular hyperkeratosis result in the development of microcomedones, and changes in follicular milieu in intensive growth of P. acnes. P. acnes secretes several proinflammatory products, which play an important role in the development of inflammation. These include lipases, proteases, hyaluronidases, and chemotactic factors. Immune response to P. acnes includes humoral and cell-mediated immunity as well as complement activation. Recent results indicate that keratinocytes and sebocytes, as major components of pilosebaceous unit, may act as immune cells and may be activated by P. acnes via toll-like receptors (TLRs) and CD14, and through CD1 molecules may recognize altered lipid content in sebum, followed by the production of inflammatory cytokines.     

Acne and sebaceous gland function

The embryologic development of the human sebaceous gland is closely related to the differentiation of the hair follicle and the epidermis. The number of sebaceous glands remains approximately the same throughout life, whereas their size tends to increase with age. The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis, as well as by other morphogens. The most apparent function of the glands is to excrete sebum. A strong increase in sebum excretion occurs a few hours after birth; this peaks during the first week and slowly subsides thereafter. A new rise takes place at about age 9 years with adrenarche and continues up to age 17 years, when the adult level is reached. The sebaceous gland is an important formation site of active androgens. Androgens are well known for their effects on sebum excretion, whereas terminal sebocyte differentiation is assisted by peroxisome proliferator-activated receptor ligands. Estrogens, glucocorticoids, and prolactin also influence sebaceous gland function. In addition, stress-sensing cutaneous signals lead to the production and release of corticotrophin-releasing hormone from dermal nerves and sebocytes with subsequent dose-dependent regulation of sebaceous nonpolar lipids. Among other lipid fractions, sebaceous glands have been shown to synthesize considerable amounts of free fatty acids without exogenous influence. Sebaceous lipids are responsible for the three-dimensional skin surface lipid organization. Contributing to the integrity of the skin barrier. They also exhibit strong innate antimicrobial activity, transport antioxidants to the skin surface, and express proinflammatory and anti-inflammatory properties. Acne in childhood has been suggested to be strongly associated with the development of severe acne during adolescence. Increased sebum excretion is a major factor in the pathophysiology of acne vulgaris. Other sebaceous gland functions are also associated with the development of acne, including sebaceous proinflammatory lipids; different cytokines produced locally; periglandular peptides and neuropeptides, such as corticotrophin-releasing hormone, which is produced by sebocytes; and substance P, which is expressed in the nerve endings at the vicinity of healthy-looking glands of acne patients. Current data indicate that acne vulgaris may be a primary inflammatory disease. Future drugs developed to treat acne not only should reduce sebum production and Propionibacterium acnes populations, but also should be targeted to reduce proinflammatory lipids in sebum, down-regulate proinflammatory signals in the pilosebaceous unit, and inhibit leukotriene B(4)-induced accumulation of inflammatory cells. They should also influence peroxisome proliferator-activated receptor regulation. Isotretinoin is still the most active available drug for the treatment of severe acne.     

痤疮易感基因的研究进展

痤疮是发生于毛囊皮脂腺的一种慢性炎症性疾病,发病机制尚不完全清楚.目前认为,主要与雄激素、皮脂分泌增多、毛囊导管的异常角化、痤疮丙酸杆菌感染、外界因素、机体的免疫反应和遗传有关.近年来研究表明,痤疮是一种多基因遗传病,尤其是重型痤疮与遗传密切相关.CYP11α、CYP17、CYP1A1、雄激素受体基因、CYP21等基因被认为是痤疮易感基因.因此,探讨痤疮的易感基因,对痤疮尤其是重型痤疮的早期诊断、治疗和预防具有重要意义.

Abstract：

Acne is a common chronic inflammatory disease affecting hair follicles and sebaceous glands with unclear pathogenesis. It is a multifactorial disease and several pathogenetic factors have been identified, including the increase of androgen and sebum excretion, follicular hyperkeratinization, infection with Propionibacterium acnes, external factors, innate immunity, genetics, etc. Latest studies have indicated that acne is a polygenic disease and there is a particularly close correlation between severe acne and heredity. Many predisposing genes have been discovered for acne, including human CYP11α gene, CYP17 gene, CYP1A1gene, androgen receptor gene, CYP21 gene, etc. Therefore, the investigation into susceptible genes for acne may be beneficial to the early diagnosis, treatment and prevention of severe acne.     

Acne: topical treatment

Acne vulgaris is a common skin disease, affecting about 70-80% of adolescents and young adults. It is a multifactorial disease of the pilosebaceous unit.(1) The influence of androgens at the onset of adolescence leads to an enlargement of the sebaceous gland and a rise in sebum production. Additional increased proliferation and altered differentiation of the follicular epithelium eventually blocks the pilosebaceous duct, leading to development of the microcomedo as the primary acne lesion. Concomitantly and subsequently, colonization with Propionibacterium acnes increases, followed by induction of inflammatory reactions from bacteria, ductal corneocytes, and sebaceous proinflammatory agents (Fig 1).(2-5)     

Hormonal therapy for acne using oral contraceptive pills

The etiology of acne vulgaris is multifactorial and complex. The four key factors involved in the development of acne include follicular plugging, inflammation, the presence and activity of Propionibacterium acnes, and sebum. Androgen hormones stimulate the sebaceous gland and promote sebum excretion. Therefore, therapies that have an overall antiandrogen effect, like combination oral contraceptive pills, may be useful in the management of acne vulgaris. Numerous combination oral contraceptive pills have been evaluated in the treatment of acne vulgaris and have been found to be effective. With a thorough understanding of their proper use and potential associated risks, these hormonal treatments may be prescribed safely and effectively to women with acne.     

痤疮易感基因的研究进展

痤疮是发生于毛囊皮脂腺的一种慢性炎症性疾病,发病机制尚不完全清楚。目前认为,主要与雄激素、皮脂分泌增多、毛囊导管的异常角化、痤疮丙酸杆菌感染、外界因素、机体的免疫反应和遗传有关。近年来研究表明,痤疮是一种多基因遗传病,尤其是重型痤疮与遗传密切相关。CYP11α、CYP17、CYP1A1、雄激素受体基因、CYP21等基因被认为是痤疮易感基因。因此,探讨痤疮的易感基因,对痤疮尤其是重型痤疮的早期诊断、治疗和预防具有重要意义。     

Acne vulgaris

Peripherally active androgens control cellular functions by binding to androgen receptors. Follicular keratinocytes and sebocytes are target cells for androgens, which, directly or indirectly, stimulate keratinocyte proliferation and the volume of sebaceous glands as well as the sebum secretion rate. Acne often begins with the adrenarche, namely with the up- regulation of adrenal synthesis of dehydroepiandrosterone sulfate, a hormone that is upstream to testosterone. The majority of acne patients exhibit normal levels of circulating androgens, while sebaceous glands from acne regions exhibit a stronger sensitivity to androgens than the sebaceous glands from other parts of the body. Hormone-like active lipids, hormones in diet and neuropeptides may also play a role in the development of acne lesions. The target of antiandrogen treatment of the skin is mainly the sebaceous gland and the primary effect is sebostasis.     

Acne. Current pathophysiologic considerations

Seborrhea, follicular hyperkeratosis, propionibacteria, and inflammatory reactions are the most important factors leading to acne. The combination of increased sebum producation and follicular hyperkeratosis facilitates an increased growth of Propionibacterium acnes. Its metabolic products lead to follicular inflammation and, in extreme cases, even to perifollicular abscesses. Sebum production is influenced by androgens, so that abnormalities in androgen levels can produce seborrhea and acne. Follicular hyperkeratosis may be triggered by a relative deficiency in linoleic acid, peroxides from sebum components, and especially by inflammatory mediators such as interleukin-1. Bacterial metabolic products such as lipases, proteases, or chemotactic factors lead to the perifollicular inflammation. This inflammation is not only a response to other pathogenetic factors, but also a cause of acne. An initial mild perifollicular inflammation can induce comedogenesis via a variety of mediators. The influence of dietary factors on the initiation and course of acne has recently received increased recognition. A connection has been postulated between acne and a high nutrients with glycemic index, as well as with milk products.     

Akne

Seborrhea, follicular hyperkeratosis, propionibacteria, and inflammatory reactions are the most important factors leading to acne. The combination of increased sebum producation and follicular hyperkeratosis facilitates an increased growth of Propionibacterium acnes. Its metabolic products lead to follicular inflammation and, in extreme cases, even to perifollicular abscesses. Sebum production is influenced by androgens, so that abnormalities in androgen levels can produce seborrhea and acne. Follicular hyperkeratosis may be triggered by a relative deficiency in linoleic acid, peroxides from sebum components, and especially by inflammatory mediators such as interleukin-1. Bacterial metabolic products such as lipases, proteases, or chemotactic factors lead to the perifollicular inflammation. This inflammation is not only a response to other pathogenetic factors, but also a cause of acne. An initial mild perifollicular infammation can induce comedogenesis via a variety of mediators. The influence of dietary factors on the initiation and course of acne has recently received increased recognition. A connection has been postulated between acne and a high nutrients with glycemic index, as well as with milk products.     

Effects of Propionibacterium acnes on various mRNA expression levels in normal human epidermal keratinocytes in vitro

Propionibacterium acnes is one of the most significant pathogenic factors of acne vulgaris. This bacteria relates to acne by various pathways. It has also been reported that P. acnes influences pro-inflammatory cytokine production in keratinocytes in vitro . However, the influence on the differentiation of keratinocytes by P. acnes has not been studied extensively. We analyzed the expression of keratinocyte differentiation-specific markers, keratins, and pro-inflammatory cytokines in normal human epidermal keratinocytes (NHEK) exposed to P. acnes in vitro . All P. acnes strains used in this study increased transglutaminase (TGase), keratin 17 (K17) and interleukin (IL) mRNA expression levels in NHEK, and decreased K1 and K10 expression levels. Some P. acnes strains increased involucrin and K6 mRNA expression levels in NHEK and decreased filaggrin, K6 and K16 expression levels in vitro . This experiment clarified that P. acnes influences the differentiation of NHEK in vitro . As a result, P. acnes influenced the expression of not only pro-inflammatory cytokines but also some keratinocyte differentiation-specific markers and keratins in NHEK. Our results suggest that P. acnes relates to acne pathogenesis by not only the induction of inflammation but also in the differentiation of keratinocytes. Moreover, it was considered that the reaction of NHEK to P. acnes may be different depending on the type of bacteria.     

The pathophysiology of acne vulgaris in children and adolescents, Part 1

Microcomedones, the earliest lesions of acne, appear at adrenarche, which typically occurs at about 8 years of age when androgens of adrenal origin begin to stimulate follicular hyperkeratosis and sebaceous hyperplasia in pilosebaceous units on the face. Comedones appear about 2 years later, when androgens of gonadal origin are produced and colonization of follicles by Propionibacterium acnes increases. Inflammatory lesions, such as pustules, papules, and nodules, are the result of the host's immune responses to P acnes; the proinflammatory cytokines are released by immunocompetent leukocytes that are recruited in response to this bacterium and its metabolic by-products. Androgens also affect the barrier function of the skin, and disturbances of barrier function may stimulate epidermal DNA synthesis. This leads to epidermal hyperplasia, which may also contribute to follicular hyperkeratosis in acne. Optimal treatment for this disorder will address these various pathophysiologic factors.     

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.     

Gene array expression profiling in acne lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling

The pathogenesis of acne has been linked to multiple factors such as increased sebum production, inflammation, follicular hyperkeratinization, and the action of Propionibacterium acnes within the follicle. In an attempt to understand the specific genes involved in inflammatory acne, we performed gene expression profiling in acne patients. Skin biopsies were obtained from an inflammatory papule and from normal skin in six patients with acne. Biopsies were also taken from normal skin of six subjects without acne. Gene array expression profiling was conducted using Affymetrix HG-U133A 2.0 arrays comparing lesional to nonlesional skin in acne patients and comparing nonlesional skin from acne patients to skin from normal subjects. Within the acne patients, 211 genes are upregulated in lesional skin compared to nonlesional skin. A significant proportion of these genes are involved in pathways that regulate inflammation and extracellular matrix remodeling, and they include matrix metalloproteinases 1 and 3, IL-8, human beta-defensin 4, and granzyme B. These data indicate a prominent role of matrix metalloproteinases, inflammatory cytokines, and antimicrobial peptides in acne lesions. These studies are the first describing the comprehensive changes in gene expression in inflammatory acne lesions and are valuable in identifying potential therapeutic targets in inflammatory acne.     

The pathophysiology of acne vulgaris in children and adolescents, part 2: Tailoring treatment

Various pathophysiologic factors are involved in the development of acne lesions, microcomedones, comedones, and inflammatory lesions. These factors include follicular hyperkeratosis, increased colonization of follicles by Propionibacterium acnes, increased sebum production, and inflammatory mediators. Optimal treatment of acne involves the use of agents that address these various underlying pathogenetic factors.     

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.     

Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation

Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.     

Expanding the microcomedone theory and acne therapeutics: Propionibacterium acnes biofilm produces biological glue that holds corneocytes together to form plug

The Propionibacterium acnes biofilm has previously been shown to exist via genomic studies and to make a biological glue which allows for adherence to follicular walls. This gylcocalyx polymer secreted by P acnes also finds its way into sebum composition where it causes the adhesiveness of keratinocytes leading to comedones. An appreciation of P acnes biofilms and secretions has implications in immunogenicity of the organism, clinical course of acne, and therapy for comedonal and inflammatory acne.     

Topical acne treatments in Europe and the issue of antimicrobial resistance

Acne vulgaris (acne) is a chronic inflammatory disease of the sebaceous gland, characterized by follicular hyperkeratinization, excessive colonization by Propionibacterium acnes (P. acnes) as well as immune reactions and inflammation. Despite an armamentarium of topical treatments available including benzoyl peroxide, retinoids and azelaic acid, topical antibiotics in monotherapies, especially erythromycin and clindamycin, are still used in Europe to treat acne. This intensive use led to antimicrobial‐resistant P. acnes and staphylococci strains becoming one of the main health issues worldwide. This is an update on the current topical acne treatments available in Europe, their mechanism of action, their potential to induce antimicrobial resistance and their clinical efficacy and safety.     

The human antimicrobial peptide dermcidin activates normal human keratinocytes

Background  The skin has evolved an epithelial defence mechanism which is characterized by antimicrobial peptides that inactivate various microorganisms and exhibit stimulatory activities bridging innate and adaptive immunity. Dermcidin (DCD) is a newly isolated antimicrobial peptide produced by the eccrine sweat glands in the skin. Recently, the DCD peptides DCD-1 and DCD-1L have been shown to display in vitro microbicidal activities against bacteria and viruses.
Objectives  Because some skin-derived antimicrobial peptides activate keratinocytes, we investigated whether DCD-1L would also trigger keratinocyte activation.
Methods  Normal human keratinocytes were used in this study. The ability of DCD-1L to induce the production of cytokines/chemokines by keratinocytes was determined by enzyme-linked immunosorbent assay, and various inhibitors were used to investigate the stimulatory mechanism of DCD-1L. Mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation were analysed by Western blotting.
Results  DCD-1L stimulated keratinocytes to generate cytokines and chemokines including tumour necrosis factor-α, interleukin-8 (CXCL8), interferon-inducible protein 10 (CXCL10) and macrophage inflammatory protein-3α (CCL20). To determine the molecular mechanism involved, we showed that DCD-1L-mediated cytokine/chemokine production was controlled by both G-protein and MAPK pathways, as evidenced by the inhibitory effects of pertussis toxin and specific inhibitors for p38 and ERK, but not for JNK, on DCD-1L-induced keratinocyte activation. Furthermore, we confirmed that DCD-1L could induce phosphorylation of p38 and ERK, and noticeably upregulated NF-κB activation.
Conclusions  Taken together, the new activity of DCD-1L to stimulate the production of cytokines/chemokines by keratinocytes provides novel evidence for the implication of DCD, beyond its microbicidal ability, in skin immunity.