- Email: [email protected]
Pathophysiological advances in acne
Annales de dermatologie (2010) 137, Special issue 5, 6-9 ISSN 0151-9638
"OOBMFTEF FUEFWnOnSnPMPHJF Organe de la Société Française de Dermatologie et de l’Association des Dermatologistes Francophones
What’s new in acne?
66792
Issue produced with the institutional support of Laboratoires dermatologiques Avène
tome 137 special issue 5 december 2010
Pathophysiological advances in acne Avancées physiopathologiques dans l’acné
N. Auffret Unité fonctionnelle de dermatologie, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75908 Paris cedex 15, France.
KEYWORDS InÁammation; P. acnes; Innate immunity; Toll like réceptor; Antimicrobial peptide
MOTS CLÉS InÁammation ; P. acnes ; Immunité innée ; Toll like récepteurs ; Peptides antimicobiens
Summary Acne is a chronic disorder caused by multiple factors. Recent advances suggest that inÁammation plays an initial role and Propionibacterium acnes plays a major role by initiating, maintaining and extending acne. © 2010 Elsevier Masson SAS. All rights reserved
Résumé L’acné est une maladie chronique dépendant de nombreux facteurs. Des données récentes laissent penser que l’inÁammation a un rôle très précoce dans la chronologie des événements et que Propionibacterium acnes joue un rôle majeur en intervenant dans le déclenchement, le maintien et la pérennisation de la maladie. © 2010 Elsevier Masson SAS. Tous droits réservés.
Correspondence. E-mail address: [email protected] (N. Auffret) © 2010 Elsevier Masson SAS. All rights reserved.
Pathophysiological Advances in Acne
Introduction Acne is a multifactorial chronic inÁammatory disease whose etiology is extremely complex. The pathophysiology of acne can be likened to a jigsaw puzzle that is being assembled piece by piece as investigative techniques evolve. Thus, experimental models, molecular biology techniques, cell cultures, and genetic advances have contributed new insights. Four main factors play a crucial role in the pathophysiology of acne, namely, sebum, changes in the pilo-sebaceous canal, Propionibacterium acnes, and inÁammation. However, the exact sequence in which these factors are involved remains unclear. Strong evidence suggests that the inÁammatory process may antedate comedo development, but other data support a role for some of these factors at all the stages of acne development.
7
• Peroxisome proliferator-activated receptors (PPAR α, β, and γ), which are intranuclear hormonal receptors that form heterodimers with RXR receptors and exert regulatory effects on sebocytes and lipogenesis [4]; • Insulin-like growth factor receptors (IGF1) and receptors for histamine 1.
Role for P. acnes in sebum production Iinuma et al. [5] showed recently that P. acnes was directly involved in increasing the production of sebum by the sebaceous glands. Hamster sebocytes exposed to insulin and various P. acnes fractions increased amounts of lipid droplets and triacylglycerol [6]. Thus, P. acnes may stimulate sebum production by the sebaceous glands, while P. acnes growth seems to be stimulated by excess sebum production, creating a vicious circle.
Excess sebum production A prerequisite to acne development is oily skin or excess sebum production [1]. At the face, the type of acne lesion has been shown to correlate with sebum production. Thus, inÁammatory lesions are more common on the cheeks, where the production of sebum is greatest. In contrast, sebum production does not correlate with comedo formation [2]. Sebum production during the course of acne is not related to a hormonal disorder. Testosterone levels are usually normal. The abnormalities are located elsewhere, in the skin. They consist of oversensitivity of various receptors, excessive reactivity of enzyme systems involved in intracellular androgen production within the sebaceous glands and/or keratinocytes, or direct or indirect effects of P. acnes.
Increased receptor sensitivity The Àrst receptor shown to be involved in acne was the androgen receptor. The enzyme type 1 5α reductase converts circulating testosterone to dihydrotestosterone, which binds to a speciÀc receptor in the sebaceous gland, activating the genes involved in sebum production. Subsequently, other receptors were shown to induce excess sebum production. The sebaceous gland behaves as an independent peripheral endocrine system that expresses the following receptors: • Receptors for neuromediators. During stress, substance P is released in large amounts by the nerve endings surrounding the pilosebaceous follicles; • Receptors for corticotrophin-releasing hormone (CRH), whose production is stimulated by P. acnes [3] and stress; • Receptors for α melanocyte-stimulating hormone (α – MSH), which is involved in lipogenesis, androgen metabolism, and cytokine release;
Role for sebum The sebum produced by the sebaceous glands of individuals with acne contains large amounts of squalenes, wax esters, and triglycerides. Sebum promotes the growth of P. acnes and supplies this organism with the nutrients it needs. The mechanisms underlying this effect remain unclear. According to one hypothesis [1], excess sebum is associated with decreased epidermal water loss, which in turn impairs protection against skin infections and increases organism growth within the pilosebaceous follicle. The sebum produced by patients with acne acts as an irritant, because P. acnes enzymes convert the triglycerides in the pilosebaceous follicle to proinflammatory free fatty acids and squalene peroxides, which stimulate keratinocytes to release proinflammatory cytokines (leukotrienes B4) [7].
Comedo formation Comedones form as a result of changes in keratinocyte proliferation and differentiation induced by regulatory modiÀcations in the expression of molecules such as keratinocyte integrins, Àlaggrin, involucrin, and some types of keratins [8-10]. Some of these changes are inÁuenced by P. acnes. Thus, in a recent in vitro study conducted by Akaza et al. [11], P. acnes was shown to promote keratinocyte differentiation by downregulating the expression of keratins 1 and 10 and upregulating the expression of interleukins, keratin 17, and transglutaminase. In acne, the Àbroblast growth factor receptor type 2 (FGF-R2) may be involved in keratinocyte differentiation, and the insulin-like growth factor receptor type 1 (IGF-R1) may regulate keratinocyte proliferation [8]. Keratinocytes also have enzyme systems
8
capable of metabolizing androgens and cholesterol. Abnormalities in the activation of some of these enzyme systems may change the intracellular levels of androgens and cholesterol, thereby inÁuencing keratinocyte differentiation and proliferation.Sebum composition may also play a crucial role. Excess sebum production inÁuences the concentrations of free fatty acids within the pilosebaceous canal. Dilution leads to an increase in the ratio of squalenewax over linoleic acid, which promotes disturbances in keratinocyte differentiation.Interleukin-1α (IL-1α) is also a major factor. In vitro, IL-1α induces the formation of comedones in pilo-sebaceous follicles obtained by microdissection and cultured for 7 days [12]. This effect can be abolished by an IL-1α receptor antagonist. In vivo, IL-1α is found in healthy skin surrounding the hair follicles and within the comedones. Comedones contain sufÀcient IL-1α to initiate an inÁammatory response when the interleukin is released into the dermis. A comedo forms when abnormal keratinocyte desquamation, in the presence of sebum and P. acnes, causes obstruction of the pilo-sebaceous canal by a corniÀed plug [13].
Propionibacterium acnes: a key culprit P. acnes is an anaerobic Gram-positive corynebacterium that is normally found on the skin. P. acnes has been suspected for many years to play a role in acne without being speciÀc of the disease. The identiÀcation of P. acnes subgroups has helped to understand the role for this organism and to explain both recent exacerbations of some forms of acne and the growing reports in recent years of P. acnes deep surgical-site infections, most notably of the eyes and trauma sites [14]. Many studies have documented a pivotal role for P. acnes in acne. This role may involve proinflammatory effects rather than infection, as no correlation has been found between P. acnes counts and acne severity. P. acnes initiates the inÁammatory response within the pilosebaceous follicle then drives the extension and perpetuation of the inÁammatory process during the course of acne. P. acnes can produce a bioÀlm [15] by encasing itself within extracellular polysaccharides, thus acting as a biological glue that binds the keratinocytes and contributes to comedo development. This bioÀ lm may explain the delayed penetration of and resistance to antimicrobial agents in acne, the need for prolonged treatment, and the tolerance of P. acnes to high antimicrobial concentrations.P. acnes stimulates humoral immunity by activating the complement via the classical and alternative (C5a) pathways, thereby inducing the production of chemotactic factors that cause an inÁux of neutrophils. Hydrolase is released, disrupting the follicular epithelium and causing inÁammation. Enzymes are produced (lipases, proteases, and hyaluronidases) that perpetuate the inÁ ammatory process.Recent evidence that P. acnes inÁuences some of the toll-like receptors (TLRs) has shed light on the many roles for this organism. P. acnes induces rapid and marked upregulation of TLR2 or TLR4 expression on the surface of keratinocytes and monocytes [16]. This effect results in
N. Auffret
the production of proinÁammatory cytokines (IL-1α, IL-8, IL-2, GM-CSF, and TNFα) [9], expression of β – defensins by keratinocytes, and release of metalloproteases. Cytokine production is inhibited by acne treatments such as zinc, nicotinamide, and adapalene [10, 17, 18]. Glucocorticoids can upregulate TLR2 expression on keratinocytes stimulated by P. acnes [19] or by proinÁammatory cytokines. These data support a role for glucocorticoids in exacerbation of acne vulgaris or in the induction of acne.P. acnes can generate oxidative stress via a TLR-independent pathway that causes inÁammation with keratinocyte apoptosis and necrosis and the production of superoxide anions [20]. This effect can be prevented by retinoids and diminished by antimicrobials. P. acnes enhances the expression of antimicrobial peptides (cathelicidin and β– defensins) and of histone H4 [21], which are major actors in innate immunity. These cationic peptides are found in many cells, including sebocytes and keratinocytes. They have antimicrobial and antiinÁammatory properties and inhibit several cytokines such as TNFα and IL-1α. Antimicrobial peptides are also found in many natural products such as milk and palm oil. Among them, lauric acid exerts antibacterial effects that are particularly interesting. In vitro studies of human skin incubated with Staphylococcus aureus, Staphylococcus epidermidis, or P. acnes in the presence of lauric acid [22] have established that P. acnes is the most sensitive of these bacteria to lauric acid. Furthermore, the minimum inhibitory concentration of lauric acid is 15 times lower than that of benzoyl peroxide, and lauric acid is devoid of toxicity for human sebocytes. Keratinocytes and sebocytes produce metalloproteases (MMPs) including gelatinases, collagenases, stromelysins, and matrilysins. MMPs are endopeptidases involved in extension of the inÁammatory response and in scar formation. The production of MMP2, MMP9, and MMP13 is increased by P. acnes and decreased by oral or topical doxycycline and isotretinoin [23,24]. • P. acnes produces coproporphyrins [25], which Áuoresce in Wood’s light, facilitating comedo count determination. The absorption peak of coproporphyrins is 415 nm. The ability of coproporphyrins to absorb light energy suggests that light therapy may hold promise in the management of acne. • P. acnes stimulates humoral immunity by inducing antibody production [26]. However, few P. acnes antigens have been identiÀed, and research into vaccine therapy is therefore still in its early stages. In addition, the only useful antibodies are directed against an acid polysaccharide. Correlations between acne severity and antibody titer elevation have been shown in only a very small number of patients. To date, no ideal animal model is available for evaluating acne treatments. Results from current models are not necessarily relevant to humans. Finally, other factors inÁuence the growth and behavior of P. acnes. In a recent study by Nakatsuji et al. [27], mice immunized via intranasal instillation of heat-inactivated P. acnes produced speciÀc antibodies and experienced prompt resolution of the inÁammatory process (IL-8, other cytokines), despite persistent bacterial growth. In the future, vaccines targeting other antigens (e.g., sialidase and TLRs) will be investigated.
Pathophysiological Advances in Acne
Conclusion The pathophysiology of acne has been partly elucidated. According to one hypothesis, in genetically susceptible individuals, the combined effect of androgens and PPAR ligands stimulates sebocytes, leading to increased sebum production and to alterations in sebum composition. This stimulating effect is potentiated by growth factors, neuromediators, and cytokines, most notably IL-1α. Its result may be increased keratinization of the infundibular portion of the pilosebaceous canal. The ability of P. acnes to stimulate innate immune responses may explain the occurrence of inÁammatory Áares in susceptible individuals. Treatment approaches that are generating research interest include inhibition of proinÁammatory mediators and innate immunity, as well as vaccination [28].
ConÁict of interests None.
References [1]
Youn SW. The role of facial sebum secretion in acne pathogenesis: facts and controversies. Clin Dermatol 2010;28:8-11. [2] Youn SW, Park ES, Lee DH, Huh CH, Park KC. Does facial sebum excretion really affect the development of acne? Br J Dermatol 2005;153:919-24. [3] Isard O, Knol AC, Castex-Rizzi N, Khammari A, Charveron M, Dréno B. Cutaneous induction of corticotropin releasing hormone by Propionibacterium acnes extracts. Dermatoendocrinol 2009;1:96-9. [4] Trivedi NR, Cong Z, Nelson AM, Albert AJ, Rosamilia LL, Sivarajah S, et al. Peroxisome proliferator-activated receptors increase human sebum production. J Invest Dermatol 2006;126:2002-9. [5] Iinuma K, Sato T, Akimoto N, Noguchi N, Sasatsu M, Nishijima S, et al. Involvement of Propionibacterium acnes in the augmentation of lipogenesis in hamster sebaceous glands in vivo and in vitro. J Invest Dermatol 2009;129:2113-9. [6] Zouboulis CC. Propionibacterium acnes and sebaceous lipogenesis: a love-hate relationship? J Invest Dermatol 2009;129:2093-6. [7] Pappas A, Johnsen S, Liu JC, Eisinge M. Sebum analysis of individuals with and without acne. Dermatoendocrinol 2009;1:157-61. [8] Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermatoendocrinol 2009;1:141-56. [9] Sugisaki H, Yamanaka K, Kakeda M, Kitagawa H, Tanaka K, Watanabe K, et al. Increased interferon-gamma, interleukin12p40 and IL-8 production in Propionibacterium acnes-treated peripheral blood mononuclear cells from patient with acne vulgaris: host response but not bacterial species is the determinant factor of the disease. J Dermatol Sci 2009;55:47-52. [10] Tenaud I, Khammari A, Dreno B. In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inÁammatory lesions. Exp Dermatol 2007;16:500-6.
9
[11] Akaza N, Akamatsu H, Kishi M, Mizutani H, Ishii I, Nakata S. Effects of Propionibacterium acnes on various mRNA expression levels in normal human epidermal keratinocytes in vitro. J Dermatol 2009;36:213-23. [12] Guy R, Green MR, Kealey T. Modeling acne in vitro. J Invest Dermatol 1996;106:176-82. [13] Cunliffe WJ, Holland DB, Jeremy A. Comedone formation: etiology, clinical presentation, and treatment. Clin Dermatol 2004;22:367-74. [14] Haidar R, Najjar M, Der Boghossian A, Tabbarah Z. Propionibacterium acnes causing delayed postoperative spine infection: Review. Scand J Infect Dis 2010;42:405-11. [15] Burkhart CG, Burkhart CN. Expanding the microcomedone theory and acne therapeutics: Propionibacterium acnes bioÀlm produces biological glue that holds corneocytes together to form plug. J Am Acad Dermatol 2007;57:722-4. [16] Jugeau S, Tenaud I, Knol AC, Jarrousse V, Quereux G, Khammari A, et al. Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol 2005;153:1105-13. [17] Grange PA, Raingeaud J, Calvez V, Dupin N. Nicotinamide inhibits Propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-kappaB and MAPK pathways. J Dermatol Sci 2009;56:106-12. [18] Jarrousse V, Castex-Rizzi N, Khammari A, Charveron M, Dréno B. Zinc salts inhibit in vitro Toll-like receptor 2 surface expression by keratinocytes. Eur J Dermatol 2007;17:492-6. [19] Shibata M, Katsuyama M, Onodera T, Ehama R, Hosoi J, Tagami H. Glucocorticoids enhance Toll-like receptor 2 expression in human keratinocytes stimulated with Propionibacterium acnes or proinflammatory cytokines. J Invest Dermatol 2009;129:375-82. [20] Grange PA, Chéreau C, Raingeaud J, Nicco C, Weill B, Dupin N, et al. Production of superoxide anions by keratinocytes initiates P. acnes-induced inÁammation of the skin. PLoS Pathog 2009;5:e1000527. [21] Lee DY, Huang CM, Nakatsuji T, Thiboutot D, Kang SA, Monestier M, et al. Gallo histone H4 is a major component of the antimicrobial action of human sebocytes. J Invest Dermatol 2009;129:2489-96. [22] Nakatsuji T, Kao MC, Fang JY, Zouboulis CC, Zhang L, Gallo RL, et al. Antimicrobial property of lauric acid against Propionibacterium acnes: its therapeutic potential for inÁammatory acne vulgaris. J Invest Dermatol 2009;129:2480-8. [23] Papakonstantinou E, Aletras AJ, Glass E, Tsogas P, Dionyssopoulos A, Adjaye J, et al. Matrix metalloproteinases of epithelial origin in facial sebum of patients with acne and their regulation by isotretinoin. J Invest Dermatol 2005;125:673-84. [24] Choi JY, Piao MS, Lee JB, Oh JS, Kim IG, Lee SC. Propionibacterium acnes stimulates pro-matrix metalloproteinase-2 expression through tumor necrosis factor-alpha in human dermal Àbroblasts. J Invest Dermatol 2008;128:846-54. [25] Romiti R, Schaller M, Jacob K, Plewig G. High-performance liquid chromatography analysis of porphyrins in Propionibacterium acnes. Arch Dermatol Res 2000;292:320-2. [26] Nakatsuji T, Liu YT, Huang CP, Zoubouis CC, Gallo RL, Huang CM. Antibodies elicited by inactivated Propionibacterium acnesbased vaccines exert protective immunity and attenuate the IL-8 production in human sebocytes: relevance to therapy for acne vulgaris. J Invest Dermatol 2008;128:2451-7. [27] Nakatsuji T, Liu YT, Huang CP, Zouboulis CC, Gallo RL, Huang CM. Vaccination targeting a surface sialidase of P. acnes: implication for new treatment of acne vulgaris. PLoS One 2008;3:29. [28] Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol 2009;18:821-32.
"OOBMFTEF FUEFWnOnSnPMPHJF Organe de la Société Française de Dermatologie et de l’Association des Dermatologistes Francophones
What’s new in acne?
66792
Issue produced with the institutional support of Laboratoires dermatologiques Avène
tome 137 special issue 5 december 2010
Pathophysiological advances in acne Avancées physiopathologiques dans l’acné
N. Auffret Unité fonctionnelle de dermatologie, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75908 Paris cedex 15, France.
KEYWORDS InÁammation; P. acnes; Innate immunity; Toll like réceptor; Antimicrobial peptide
MOTS CLÉS InÁammation ; P. acnes ; Immunité innée ; Toll like récepteurs ; Peptides antimicobiens
Summary Acne is a chronic disorder caused by multiple factors. Recent advances suggest that inÁammation plays an initial role and Propionibacterium acnes plays a major role by initiating, maintaining and extending acne. © 2010 Elsevier Masson SAS. All rights reserved
Résumé L’acné est une maladie chronique dépendant de nombreux facteurs. Des données récentes laissent penser que l’inÁammation a un rôle très précoce dans la chronologie des événements et que Propionibacterium acnes joue un rôle majeur en intervenant dans le déclenchement, le maintien et la pérennisation de la maladie. © 2010 Elsevier Masson SAS. Tous droits réservés.
Correspondence. E-mail address: [email protected] (N. Auffret) © 2010 Elsevier Masson SAS. All rights reserved.
Pathophysiological Advances in Acne
Introduction Acne is a multifactorial chronic inÁammatory disease whose etiology is extremely complex. The pathophysiology of acne can be likened to a jigsaw puzzle that is being assembled piece by piece as investigative techniques evolve. Thus, experimental models, molecular biology techniques, cell cultures, and genetic advances have contributed new insights. Four main factors play a crucial role in the pathophysiology of acne, namely, sebum, changes in the pilo-sebaceous canal, Propionibacterium acnes, and inÁammation. However, the exact sequence in which these factors are involved remains unclear. Strong evidence suggests that the inÁammatory process may antedate comedo development, but other data support a role for some of these factors at all the stages of acne development.
7
• Peroxisome proliferator-activated receptors (PPAR α, β, and γ), which are intranuclear hormonal receptors that form heterodimers with RXR receptors and exert regulatory effects on sebocytes and lipogenesis [4]; • Insulin-like growth factor receptors (IGF1) and receptors for histamine 1.
Role for P. acnes in sebum production Iinuma et al. [5] showed recently that P. acnes was directly involved in increasing the production of sebum by the sebaceous glands. Hamster sebocytes exposed to insulin and various P. acnes fractions increased amounts of lipid droplets and triacylglycerol [6]. Thus, P. acnes may stimulate sebum production by the sebaceous glands, while P. acnes growth seems to be stimulated by excess sebum production, creating a vicious circle.
Excess sebum production A prerequisite to acne development is oily skin or excess sebum production [1]. At the face, the type of acne lesion has been shown to correlate with sebum production. Thus, inÁammatory lesions are more common on the cheeks, where the production of sebum is greatest. In contrast, sebum production does not correlate with comedo formation [2]. Sebum production during the course of acne is not related to a hormonal disorder. Testosterone levels are usually normal. The abnormalities are located elsewhere, in the skin. They consist of oversensitivity of various receptors, excessive reactivity of enzyme systems involved in intracellular androgen production within the sebaceous glands and/or keratinocytes, or direct or indirect effects of P. acnes.
Increased receptor sensitivity The Àrst receptor shown to be involved in acne was the androgen receptor. The enzyme type 1 5α reductase converts circulating testosterone to dihydrotestosterone, which binds to a speciÀc receptor in the sebaceous gland, activating the genes involved in sebum production. Subsequently, other receptors were shown to induce excess sebum production. The sebaceous gland behaves as an independent peripheral endocrine system that expresses the following receptors: • Receptors for neuromediators. During stress, substance P is released in large amounts by the nerve endings surrounding the pilosebaceous follicles; • Receptors for corticotrophin-releasing hormone (CRH), whose production is stimulated by P. acnes [3] and stress; • Receptors for α melanocyte-stimulating hormone (α – MSH), which is involved in lipogenesis, androgen metabolism, and cytokine release;
Role for sebum The sebum produced by the sebaceous glands of individuals with acne contains large amounts of squalenes, wax esters, and triglycerides. Sebum promotes the growth of P. acnes and supplies this organism with the nutrients it needs. The mechanisms underlying this effect remain unclear. According to one hypothesis [1], excess sebum is associated with decreased epidermal water loss, which in turn impairs protection against skin infections and increases organism growth within the pilosebaceous follicle. The sebum produced by patients with acne acts as an irritant, because P. acnes enzymes convert the triglycerides in the pilosebaceous follicle to proinflammatory free fatty acids and squalene peroxides, which stimulate keratinocytes to release proinflammatory cytokines (leukotrienes B4) [7].
Comedo formation Comedones form as a result of changes in keratinocyte proliferation and differentiation induced by regulatory modiÀcations in the expression of molecules such as keratinocyte integrins, Àlaggrin, involucrin, and some types of keratins [8-10]. Some of these changes are inÁuenced by P. acnes. Thus, in a recent in vitro study conducted by Akaza et al. [11], P. acnes was shown to promote keratinocyte differentiation by downregulating the expression of keratins 1 and 10 and upregulating the expression of interleukins, keratin 17, and transglutaminase. In acne, the Àbroblast growth factor receptor type 2 (FGF-R2) may be involved in keratinocyte differentiation, and the insulin-like growth factor receptor type 1 (IGF-R1) may regulate keratinocyte proliferation [8]. Keratinocytes also have enzyme systems
8
capable of metabolizing androgens and cholesterol. Abnormalities in the activation of some of these enzyme systems may change the intracellular levels of androgens and cholesterol, thereby inÁuencing keratinocyte differentiation and proliferation.Sebum composition may also play a crucial role. Excess sebum production inÁuences the concentrations of free fatty acids within the pilosebaceous canal. Dilution leads to an increase in the ratio of squalenewax over linoleic acid, which promotes disturbances in keratinocyte differentiation.Interleukin-1α (IL-1α) is also a major factor. In vitro, IL-1α induces the formation of comedones in pilo-sebaceous follicles obtained by microdissection and cultured for 7 days [12]. This effect can be abolished by an IL-1α receptor antagonist. In vivo, IL-1α is found in healthy skin surrounding the hair follicles and within the comedones. Comedones contain sufÀcient IL-1α to initiate an inÁammatory response when the interleukin is released into the dermis. A comedo forms when abnormal keratinocyte desquamation, in the presence of sebum and P. acnes, causes obstruction of the pilo-sebaceous canal by a corniÀed plug [13].
Propionibacterium acnes: a key culprit P. acnes is an anaerobic Gram-positive corynebacterium that is normally found on the skin. P. acnes has been suspected for many years to play a role in acne without being speciÀc of the disease. The identiÀcation of P. acnes subgroups has helped to understand the role for this organism and to explain both recent exacerbations of some forms of acne and the growing reports in recent years of P. acnes deep surgical-site infections, most notably of the eyes and trauma sites [14]. Many studies have documented a pivotal role for P. acnes in acne. This role may involve proinflammatory effects rather than infection, as no correlation has been found between P. acnes counts and acne severity. P. acnes initiates the inÁammatory response within the pilosebaceous follicle then drives the extension and perpetuation of the inÁammatory process during the course of acne. P. acnes can produce a bioÀlm [15] by encasing itself within extracellular polysaccharides, thus acting as a biological glue that binds the keratinocytes and contributes to comedo development. This bioÀ lm may explain the delayed penetration of and resistance to antimicrobial agents in acne, the need for prolonged treatment, and the tolerance of P. acnes to high antimicrobial concentrations.P. acnes stimulates humoral immunity by activating the complement via the classical and alternative (C5a) pathways, thereby inducing the production of chemotactic factors that cause an inÁux of neutrophils. Hydrolase is released, disrupting the follicular epithelium and causing inÁammation. Enzymes are produced (lipases, proteases, and hyaluronidases) that perpetuate the inÁ ammatory process.Recent evidence that P. acnes inÁuences some of the toll-like receptors (TLRs) has shed light on the many roles for this organism. P. acnes induces rapid and marked upregulation of TLR2 or TLR4 expression on the surface of keratinocytes and monocytes [16]. This effect results in
N. Auffret
the production of proinÁammatory cytokines (IL-1α, IL-8, IL-2, GM-CSF, and TNFα) [9], expression of β – defensins by keratinocytes, and release of metalloproteases. Cytokine production is inhibited by acne treatments such as zinc, nicotinamide, and adapalene [10, 17, 18]. Glucocorticoids can upregulate TLR2 expression on keratinocytes stimulated by P. acnes [19] or by proinÁammatory cytokines. These data support a role for glucocorticoids in exacerbation of acne vulgaris or in the induction of acne.P. acnes can generate oxidative stress via a TLR-independent pathway that causes inÁammation with keratinocyte apoptosis and necrosis and the production of superoxide anions [20]. This effect can be prevented by retinoids and diminished by antimicrobials. P. acnes enhances the expression of antimicrobial peptides (cathelicidin and β– defensins) and of histone H4 [21], which are major actors in innate immunity. These cationic peptides are found in many cells, including sebocytes and keratinocytes. They have antimicrobial and antiinÁammatory properties and inhibit several cytokines such as TNFα and IL-1α. Antimicrobial peptides are also found in many natural products such as milk and palm oil. Among them, lauric acid exerts antibacterial effects that are particularly interesting. In vitro studies of human skin incubated with Staphylococcus aureus, Staphylococcus epidermidis, or P. acnes in the presence of lauric acid [22] have established that P. acnes is the most sensitive of these bacteria to lauric acid. Furthermore, the minimum inhibitory concentration of lauric acid is 15 times lower than that of benzoyl peroxide, and lauric acid is devoid of toxicity for human sebocytes. Keratinocytes and sebocytes produce metalloproteases (MMPs) including gelatinases, collagenases, stromelysins, and matrilysins. MMPs are endopeptidases involved in extension of the inÁammatory response and in scar formation. The production of MMP2, MMP9, and MMP13 is increased by P. acnes and decreased by oral or topical doxycycline and isotretinoin [23,24]. • P. acnes produces coproporphyrins [25], which Áuoresce in Wood’s light, facilitating comedo count determination. The absorption peak of coproporphyrins is 415 nm. The ability of coproporphyrins to absorb light energy suggests that light therapy may hold promise in the management of acne. • P. acnes stimulates humoral immunity by inducing antibody production [26]. However, few P. acnes antigens have been identiÀed, and research into vaccine therapy is therefore still in its early stages. In addition, the only useful antibodies are directed against an acid polysaccharide. Correlations between acne severity and antibody titer elevation have been shown in only a very small number of patients. To date, no ideal animal model is available for evaluating acne treatments. Results from current models are not necessarily relevant to humans. Finally, other factors inÁuence the growth and behavior of P. acnes. In a recent study by Nakatsuji et al. [27], mice immunized via intranasal instillation of heat-inactivated P. acnes produced speciÀc antibodies and experienced prompt resolution of the inÁammatory process (IL-8, other cytokines), despite persistent bacterial growth. In the future, vaccines targeting other antigens (e.g., sialidase and TLRs) will be investigated.
Pathophysiological Advances in Acne
Conclusion The pathophysiology of acne has been partly elucidated. According to one hypothesis, in genetically susceptible individuals, the combined effect of androgens and PPAR ligands stimulates sebocytes, leading to increased sebum production and to alterations in sebum composition. This stimulating effect is potentiated by growth factors, neuromediators, and cytokines, most notably IL-1α. Its result may be increased keratinization of the infundibular portion of the pilosebaceous canal. The ability of P. acnes to stimulate innate immune responses may explain the occurrence of inÁammatory Áares in susceptible individuals. Treatment approaches that are generating research interest include inhibition of proinÁammatory mediators and innate immunity, as well as vaccination [28].
ConÁict of interests None.
References [1]
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