Qiang Ju

New developments in our understanding of acne pathogenesis and treatment

Abstract:  Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005–2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll‐like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR‐2, may stimulate the secretion of cytokines, such as interleukin (IL)‐6 and IL‐8 by follicular keratinocytes and IL‐8 and ‐12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL‐1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5α‐dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future.

Acne-associated syndromes: models for better understanding of acne pathogenesis.

Acne, one of the most common skin disorders, is also a cardinal component of many systemic diseases or syndromes. Their association illustrates the nature of these diseases and is indicative of the pathogenesis of acne. Congenital adrenal hyperplasia (CAH) and seborrhoea‐acne‐hirsutism‐androgenetic alopecia (SAHA) syndrome highlight the role of androgen steroids, while polycystic ovary (PCO) and hyperandrogenism‐insulin resistance‐acanthosis nigricans (HAIR‐AN) syndromes indicate insulin resistance in acne. Apert syndrome with increased fibroblast growth factor receptor 2 (FGFR2) signalling results in follicular hyperkeratinization and sebaceous gland hypertrophy in acne. Synovitis‐acne‐pustulosis‐hyperostosis‐osteitis (SAPHO) and pyogenic arthritis‐pyoderma gangrenosum‐acne (PAPA) syndromes highlight the attributes of inflammation to acne formation. Advances in the understanding of the manifestation and molecular mechanisms of these syndromes will help to clarify acne pathogenesis and develop novel therapeutic modalities.

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin alters sebaceous gland cell differentiation in vitro

Abstract:  Chloracne is a characteristic marker of intoxication by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) or related compounds. Decreased lipogenesis is a prominent clinical sign in this disease. However, the activity of dioxins on human sebaceous glands is still unclear. In this study, the effects of TCDD on sebaceous gland differentiation were studied both in human skin samples maintained ex vivo and in cultured SZ95 sebocytes. Aryl hydrocarbon receptor (AhR) protein expression, the receptor for dioxin, was detected in SZ95 sebocytes. Its expression was markedly inhibited by TCDD. Furthermore, we detected a reduced release of neutral lipids (10−10–10−8 m; P < 0.001) and decreased expression of epithelial membrane antigen and keratin 7, all of which are specific markers of sebaceous differentiation. Markedly, increased expression of the keratinocyte differentiation marker keratin 10 and of peroxisome proliferators‐activated receptor‐δ was assessed in SZ95 sebocytes treated with TCDD. To corroborate these in vitro data, an ex vivo sebaceous gland‐rich skin culture model was investigated. Obvious shrinkage of sebaceous glands with sebaceous duct hyperplasia and increased expression of keratin 10 in the atrophic sebaceous glands were observed on the 5th day of TCDD treatment. In conclusion, TCDD affects the differentiation of sebaceous gland cells probably by switching human sebaceous into keratinocyte‐like differentiation. In addition and together with the results of a parallel study (J Dermatol Sci 58, 2010, 211), we provide evidence that TCDD effects on human sebocytes are mediated through the AhR signalling pathway.

Beyond acne: Current aspects of sebaceous gland biology and function

The sebaceous gland is most commonly found in association with a hair follicle. Its traditional function is the holocrine production of sebum, a complex mixture of lipids, cell debris, and other rather poorly characterized substances. Due to the gland’s central role in acne pathogenesis, early research had focused on its lipogenic activity. Less studied aspects of the sebaceous gland, such as stem cell biology, the regulation of cellular differentiation by transcription factors, the significance of specific lipid fractions, the endocrine and specially the neuroendocrine role of the sebaceous gland, and its contribution to the innate immunity, the detoxification of the skin, and skin aging have only recently attracted the attention of researchers from different disciplines. Here, we summarize recent multidisciplinary progress in sebaceous gland research and discuss how sebaceous gland research may stimulate the development of novel therapeutic strategies targeting specific molecular pathways of the pathogenesis of skin diseases.

Culture of human sebocytes in vitro

Acne and seborrhoea are sebaceous gland-related diseases and are also exclusively human diseases. Therefore, fundamental research on human sebaceous cell function and control requires human models in vitro. The human sebocyte culture model was first introduced in 1989. Cultured human sebocytes have been shown to preserve important sebocytic characteristics, although they undergo an incomplete terminal differentiation in vitro. Over the years, modifications of the technique have improved the culture of human sebocytes in vitro, but the primary cultured sebocytes can still be maintained for no more than 6 passages in vitro. The immortalized human sebaceous gland cell lines SZ95, SEB-1 and Seb-E6E7 have been developed in recent years, which make it possible to get a large number of sebocytes from the sams donor culture. Cultured human sebocytes in vitro has become a useful tool in studying sebaceous gland activity and regulation, and understanding the pathophysiological mechanisms and treatment of acne and other sebaceous gland related diseases.

Benzo(a)pyrene induces interleukin (IL)-6 production and reduces lipid synthesis in human SZ95 sebocytes via the aryl hydrocarbon receptor signaling pathway

In this study, we determined the effects of benzo(a)pyrene (BaP) on the expression of aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1 (CYP1A1), and assessed the action of BaP on inflammatory cytokine expression and lipid synthesis in SZ95 sebocytes in vitro. BaP (10(-8), 10(-7), 10(-6) and 10(-5)M) was not cytotoxic for SZ95 sebocytes after 24h exposure. Expression of AhR was promoted in mRNA lever, while was inhibited in protein lever after BaP (10(-5)M) exposure. CYP1A1 expression was up-regulated in both mRNA and protein levels. BaP (10(-5)M) exerted a stimulatory action on interleukin (IL)-6 secretion, while a dose-dependently inhibitory effect on lipid synthesis from 10(-8)M to 10(-5)M in SZ95 sebocytes. Both actions were partly antagonized in AhR-knockdowned SZ95 sebocytes. This study demonstrates that BaP can activate AhR signaling pathway, and exhibits pro-inflammatory effects and inhibitory effects on sebum production in human sebocytes.

Endocrine-disrupting chemicals and skin manifestations

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that have the ability to disrupt the production and actions of hormones through direct or indirect interaction with hormone receptors, thus acting as agonists or antagonists. Human health is affected after either individual occupation or dietary and environmental exposure to EDCs. On the other hand, skin is one of the largest organs of the body and its main function is protection from noxious substances. EDCs perturb the endocrine system, and they are also carcinogenic, immunotoxic, and hepatotoxic to human skin. In addition, their effects on keratinocytes, melanocytes, sebocytes, inflammatory and immunological cells, and skin stem cells produce inflammatory and allergic skin diseases, chloracne, disorders of skin pigmentation, skin cancer, and skin aging. Mechanisms, which EDCs use to induce these skin disorders are complicated, and involve the interference of endogenous hormones and most importantly the activation of the aryl hydrocarbon receptor signal pathway. Further studies on EDCs and skin diseases are necessary to elucidate these mechanisms.

Clinical and histopathological characteristics in patients with scarring folliculitis type of acne inversa

ABSTRACT Objective: This study was designed to study the clinical and histopathological characteristics of patients with the scarring folliculitis type acne inversa in Chinese population. Methods: A total of 21 patients with acne inversa and 6 controls without known dermatological disease were recruited from outpatient department of dermatology and orthopedic surgery. Two-millimeter punch biopsies were taken from 8 patients with acne inversa and 6 controls, fixed in formalin, embedded in paraffin and stained with haematoxylin and eosin prior to histopathological analysis. Results: There were 12 patients (57.14%) belonging to the scarring folliculitis type presented with double comedones, papules, nodules, depressed scars, and were mainly Hurley stage I (66.67%). Many of the scarring folliculitis type were smokers (58.33%), some had a history of occupational exposure (41.67%) and some were overweight (50%), the mean BMI of which is 25.18±3.16 kg/m2. Histopathological changes such as perifollicular inflammation can be observed in scarring folliculitis type of acne inversa and controls as well. However, epidermal hyperplasia, follicular hyperplasia, sebaceous gland disappearance, destruction of hair follicle and sebaceous gland, collagen hyperplasia, perivascular inflammation, granulomatous inflammation, Micro thrombus were only seen in scarring folliculitis type. The mean surface area in patients (8073.36±15798.43 μm2) was smaller than that in controls (302059.08±502813.78 μm2), with statistically significant difference. (P = 0.024). Conclusion: The scarring folliculitis type in acne inversa in Chinese population could be characterized by depressed scars, double-ended comedones, epidermal cysts and had high proportion of smokers, or occupational exposure with lower Hurley stage, as well as diminished sebaceous gland. Further studies are needed to clarify the relations between the clinical subtypes of acne inversa and their corresponding genetypes.

In vivo reflectance confocal microscopy in daily practice: Image features correlated to histopathology

In vivo reflectance confocal microscopy (RCM) represents a promising technique for noninvasive visualization of skin lesions. In the clinical daily practice, doctors want to know the relationship between the RCM images and the skin pathological changes.

Aryl Hydrocarbon Receptor Modulates the Expression of TNF-α and IL-8 in Human Sebocytes via the MyD88-p65NF-κB/p38MAPK Signaling Pathways

Activation of Toll-like receptor (TLR)-2 and subsequent inflammatory response contribute to lesion development in acne vulgaris. A cross-talk between aryl hydrocarbon receptor (AhR), a cytosolic receptor protein that responds to environmental and physiological stress, and TLRs has recently been reported. In this study, we explored the possible role of AhR in the effects induced on cultured human SZ95 sebocytes by peptidoglycan (PGN), a classic TLR2 agonist. PGN-induced secretion of inflammatory factors TNF-α and IL-8 in human SZ95 sebocytes was suppressed after knockdown of AhR and pretreatment with the AhR antagonist CH223191. In addition, the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhanced TNF-α and IL-8 secretion in PGN-pretreated sebocytes. Furthermore, PGN-induced expression of myeloid differentiation factor 88 (MyD88), phospho-p38MAPK (p-p38MAPK), and p-p65NF-κB was strengthened by TCDD and repressed by CH223191. AhR inhibition by transfecting shRNA blocked the ability of PGN to stimulate phosphorylation of p38MAPK and p65NF-κB in SZ95 sebocytes. Overall, these data demonstrate that AhR is able to modulate PGN-induced expression of TNF-α and IL-8 in human SZ95 sebocytes involving the MyD88-p65NF-κB/p38MAPK signaling pathway, which probably indicates a new mechanism in TLR2-mediated acne.