Toll-like receptor 2 activation and comedogenesis: implications for the pathogenesis of acne

Annals of Occupational and Environmental Medicine

Joanne Louise Selway¹  Tomasz Kurczab¹  Terence Kealey¹  Kenneth Langlands¹ 

[1] The Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK

关键词: Keratinocytes;    Interleukin-1alpha;    Peptidoglycan;    Toll-like receptors;    Acne vulgaris;   

Others  :  814206
DOI  :  10.1186/1471-5945-13-10

 received in 2013-03-22, accepted in 2013-08-28,  发布年份 2013

【 摘 要 】

Background

Acne is a common disorder of the human pilosebaceous unit, yet the mechanisms underlying hyperkeratinisation and subsequent inflammation (comedogenesis) remain to be determined, although cutaneous pathogens are implicated. Previously, it was reported that the release of the cytokine interleukin-1α (IL-1α) by keratinocytes of the sebaceous duct was pivotal in the life cycle of the comedone, mediating both its development and its spontaneous resolution. Toll-like receptors are a family of molecules that recognise pathogen associated molecular patterns (PAMPs) presented by microorganisms, initiating a signalling cascade terminating in the release of antimicrobial compounds and cytokines.

Methods

We used ex vivo sebaceous gland and primary monolayer keratinocyte culture, alongside ELISAs, immunohistochemistry, Western blotting and RT-PCR to investigate the contribution of TLR activation to acne pathogenesis.

Results

We found TLR2 to be expressed in basal and infundibular keratinocytes, and sebaceous glands, and its activation provoked the release of IL-1α from primary human keratinocytes in vitro. The exposure of microdissected human sebaceous glands to PAMPs specific for TLR2 in vitro resulted in a pattern of IL-1α like cornification after seven days of exposure.

Conclusions

TLR activation and secretion of IL-1α from keratinocytes may be initiating steps in comedogenesis and, therefore, critical to the pathophysiology of acne.

【 授权许可】

   
2013 Selway et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ingham E, Eady EA, Goodwin CE, Cove JH, Cunliffe WJ: Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris. J Invest Dermatol 1992, 98:895-901.
• [2]Guy R, Green MR, Kealey T: Modeling acne in vitro. J Invest Dermatol 1996, 106:176-182.
• [3]Downie MM, Sanders DA, Kealey T: Modelling the remission of individual acne lesions in vitro. Br J Dermatol 2002, 147:869-878.
• [4]Wolff K, Stingl G: The Langerhans cell. J Invest Dermatol 1983, 80(Suppl):17s-21s.
• [5]Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996, 86:973-983.
• [6]McInturff JE, Modlin RL, Kim J: The role of toll-like receptors in the pathogenesis and treatment of dermatological disease. J Invest Dermatol 2005, 125:1-8.
• [7]Heymann WR: Toll-like receptors in acne vulgaris. J Am Acad Dermatol 2006, 55:691-692.
• [8]Nishimura M, Naito S: Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull 2005, 28:886-892.
• [9]Lai Y, Gallo R: Toll-like receptors in skin infectious and inflammatory diseases. Infec dis drug targets 2008, 8:144.
• [10]Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004, 4:499-511.
• [11]Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 2010, 11:373-384.
• [12]Graham GM, Farrar MD, Cruse-Sawyer JE, Holland KT, Ingham E: Proinflammatory cytokine production by human keratinocytes stimulated with Propionibacterium acnes and P. acnes GroEL. Br J Dermatol 2004, 150:421-428.
• [13]Sumikawa Y, Asada H, Hoshino K, Azukizawa H, Katayama I, Akira S, Itami S: Induction of [beta]-defensin 3 in keratinocytes stimulated by bacterial lipopeptides through toll-like receptor 2. Microbes Infect 2006, 8:1513-1521.
• [14]Kim J, Ochoa M-T, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, Brightbill HD, Holland D, Cunliffe WJ, Akira S, et al.: Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002, 169:1535-1541.
• [15]Kim J: Review of the innate immune response in acne vulgaris: activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. Dermatol 2005, 211:193-198.
• [16]Guy R, Kealey T: The effects of inflammatory cytokines on the isolated human sebaceous infundibulum. J Invest Dermatol 1998, 110:410-415.
• [17]Song PI, Park YM, Abraham T, Harten B, Zivony A, Neparidze N, Armstrong CA, Ansel JC: Human keratinocytes express functional CD14 and toll-like receptor 4. J Invest Dermatol 2002, 119:424-432.
• [18]Jugeau S, Tenaud I, Knol AC, Jarrousse V, Quereux G, Khammari A, Dreno B: Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol 2005, 153:1105-1113.
• [19]Baker BS, Ovigne J-M, Powles AV, Corcoran S, Fry L: Normal keratinocytes express toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 2003, 148:670-679.
• [20]Curry JL, Qin JZ, Bonish B, Carrick R, Bacon P, Panella J, Robinson J, Nickoloff BJ: Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 2003, 127:178-186.
• [21]Pivarcsi A, Bodai L, Rethi B, Kenderessy-Szabo A, Koreck A, Szell M, Beer Z, Bata-Csorgoo Z, Magocsi M, Rajnavolgyi E, et al.: Expression and function of toll-like receptors 2 and 4 in human keratinocytes. Int Immunol 2003, 15:721-730.
• [22]Lebre MC, van der Aar AM, van Baarsen L, van Capel TM, Schuitemaker JH, Kapsenberg ML, de Jong EC: Human keratinocytes express functional toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 2007, 127:331-341.
• [23]Miller LS, Sorensen OE, Liu PT, Jalian HR, Eshtiaghpour D, Behmanesh BE, Chung W, Starner TD, Kim J, Sieling PA, et al.: TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J Immunol 2005, 174:6137-6143.
• [24]Ingham E, Walters CE, Eady EA, Cove JH, Kearney JN, Cunliffe WJ: Inflammation in acne vulgaris: failure of skin micro-organisms to modulate keratinocyte interleukin 1 alpha production in vitro. Dermatol 1998, 196:86-88.
• [25]Nagy I, Pivarcsi A, Koreck A, Szell M, Urban E, Kemeny L: Distinct strains of Propionibacterium acnes induce selective human beta-defensin-2 and interleukin-8 expression in human keratinocytes through toll-like receptors. J Invest Dermatol 2005, 124:931-938.
• [26]Georgel P, Crozat K, Lauth X, Makrantonaki E, Seltmann H, Sovath S, Hoebe K, Du X, Rutschmann S, Jiang Z, et al.: A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria. Infect Immun 2005, 73:4512-4521.
• [27]Oeff MK, Seltmann H, Hiroi N, Nastos A, Makrantonaki E, Bornstein SR, Zouboulis CC: Differential regulation of toll-like receptor and CD14 pathways by retinoids and corticosteroids in human sebocytes. Dermatol 2006, 213:266.
• [28]Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ: Inflammatory events are involved in acne lesion initiation. J Invest Dermatol 2003, 121:20-27.
• [29]Nagy I, Pivarcsi A, Kis K, Koreck A, Bodai L, McDowell A, Seltmann H, Patrick S, Zouboulis CC, Kemeny L: Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes. Microbes Infect 2006, 8:2195-2205.
• [30]Choi JJ, Park MY, Lee HJ, Yoon DY, Lim Y, Hyun JW, Zouboulis CC, Jin M: TNF-alpha increases lipogenesis via JNK and PI3K/Akt pathways in SZ95 human sebocytes. J Dermatol Sci 2012, 65:179-188.
• [31]Melnik B: Dietary intervention in acne: attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinol 2012, 4:20-32.
• [32]Jahns AC, Lundskog B, Ganceviciene R, Palmer RH, Golovleva I, Zouboulis CC, McDowell A, Patrick S, Alexeyev OA: An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case–control study. Br J Dermatol 2012, 167:50-58.
• [33]Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Carrera P, Inhester T, Schultze JL, Hoch M: FOXO-dependent regulation of innate immune homeostasis. Nature 2010, 463:369-373.