Tumour Necrosis Factor Alpha-induced Protein 3 Negatively Regulates Cutibacterium acnes-induced Innate Immune Events in Epidermal Keratinocytes
Keywords:TNFAIP3, microbiota, Cutibacterium acnes, acne vulgaris, innate immunity
Human epidermal keratinocytes sense the presence of human skin microbiota through pathogen recognition receptors, such as toll-like receptors, and induce innate immune and inflammatory events. In healthy epidermis there is an absence of inflammation despite the continuous presence of cutaneous microbes, which is evidence of an effective immune regulatory mechanism. The aim of this study was to investigate tumour necrosis factor alpha-induced protein 3 (TNFAIP3), a negative regulator of toll-like receptor and nuclear factor kappa B signalling pathways, and its role in these regulatory events. A broad spectrum of toll-like receptor ligands induced TNFAIP3 expression, as did live Cutibacterium acnes, which is involved in the pathogenesis of acne. Changes in bacterium-induced, dose-dependent TNFAIP3 expression were Jun kinase- and nuclear factor kappa B-dependent, and resulted in altered cytokine and chemokine levels in in vitro cultured human keratinocytes. In acne lesions, TNFAIP3 mRNA expression was elevated compared with non-lesional skin samples from the same individuals. These results suggest that TNFAIP3 may have a general role in fine regulation of microbiota-induced cutaneous immune homeostasis.
Eyerich S, Eyerich K, Traidl-Hoffmann C, Biedermann T. Cutaneous barriers and skin immunity: differentiating a connected network. Trends Immunol 2018; 39: 315-327.
Gallo RL, Nakatsuji T. Microbial symbiosis with the innate immune defense system of the skin. J Invest Dermatol 2011; 131: 1974-1980.
de Koning HD, Rodijk-Olthuis D, van Vlijmen-Willems IM, Joosten LA, Netea MG, Schalkwijk J, et al. A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis. J Invest Dermatol 2010; 130: 2611-2620.
Pivarcsi A, Kemeny L, Dobozy A. Innate immune functions of the keratinocytes. A review. Acta Microbiol Immunol Hung 2004; 51: 303-310.
Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 2005; 5: 446-458.
Oh J, Conlan S, Polley EC, Segre JA, Kong HH. Shifts in human skin and nares microbiota of healthy children and adults. Genome Med 2012; 4: 77.
Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol 2011; 9: 244-253.
Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 2002; 169: 1535-1541.
Pivarcsi A, Bodai L, Rethi B, Kenderessy-Szabo A, Koreck A, Szell M, et al. Expression and function of Toll-like receptors 2 and 4 in human keratinocytes. Int Immunol 2003; 15: 721-730.
Nguyen CT, Sah SK, Zouboulis CC, Kim TY. Inhibitory effects of superoxide dismutase 3 on Propionibacterium acnes-induced skin inflammation. Sci Rep 2018; 8: 4024.
Wang YY, Ryu AR, Jin S, Jeon YM, Lee MY. Chlorin e6-mediated photodynamic therapy suppresses P. acnes-induced inflammatory response via NFkappaB and MAPKs signaling pathway. PLoS One 2017; 12: e0170599.
Pretsch A, Nagl M, Schwendinger K, Kreiseder B, Wiederstein M, Pretsch D, et al. Antimicrobial and anti-inflammatory activities of endophytic fungi Talaromyces wortmannii extracts against acne-inducing bacteria. PLoS One 2014; 9: e97929.
Simanski M, Erkens AS, Rademacher F, Harder J. Staphylococcus epidermidis-induced interleukin-1 beta and human beta-defensin-2 expression in human keratinocytes is regulated by the host molecule A20 (TNFAIP3). Acta Derm Venereol 2019; 99: 181-187.
Danis J, Janovak L, Guban B, Goblos A, Szabo K, Kemeny L, et al. Differential inflammatory-response kinetics of human keratinocytes upon cytosolic RNA- and DNA-fragment induction. Int J Mol Sci 2018; 19: 774.
Megyeri K, Orosz L, Bolla S, Erdei L, Razga Z, Seprenyi G, et al. Propionibacterium acnes induces autophagy in keratinocytes: involvement of multiple mechanisms. J Invest Dermatol 2018; 138: 750-759.
Tax G, Urban E, Palotas Z, Puskas R, Konya Z, Biro T, et al. Propionic acid produced by propionibacterium acnes strains contributes to their pathogenicity. Acta Derm Venereol 2016; 96: 43-49.
Bolla BS, Erdei L, Urban E, Burian K, Kemeny L, Szabo K. Cutibacterium acnes regulates the epidermal barrier properties of HPV-KER human immortalized keratinocyte cultures. Sci Rep 2020; 10: 12815.
Trivedi NR, Gilliland KL, Zhao W, Liu W, Thiboutot DM. Gene array expression profiling in acne lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling. J Invest Dermatol 2006; 126: 1071-1079.
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.
Lheure C, Grange PA, Ollagnier G, Morand P, Desire N, Sayon S, et al. TLR-2 Recognizes propionibacterium acnes CAMP factor 1 from highly inflammatory strains. PLoS One 2016; 11: e0167237.
Sohn KC, Back SJ, Choi DK, Shin JM, Kim SJ, Im M, et al. The inhibitory effect of A20 on the inflammatory reaction of epidermal keratinocytes. Int J Mol Med 2016; 37: 1099-1104.
Tiruppathi C, Soni D, Wang DM, Xue J, Singh V, Thippegowda PB, et al. The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. Nat Immunol 2014; 15: 239-247.
Lai TY, Wu SD, Tsai MH, Chuang EY, Chuang LL, Hsu LC, et al. Transcription of Tnfaip3 is regulated by NF-kappaB and p38 via C/EBPbeta in activated macrophages. PLoS One 2013; 8: e73153.
Szabo K, Erdei L, Bolla BS, Tax G, Biro T, Kemeny L. Factors shaping the composition of the cutaneous microbiota. Br J Dermatol 2017; 176: 344-351.
Szegedi A, Dajnoki Z, Biro T, Kemeny L, Torocsik D. Acne: transient arrest in the homeostatic host-microbiota dialog? Trends Immunol 2019; 40: 873-876.
Kollisch G, Kalali BN, Voelcker V, Wallich R, Behrendt H, Ring J, et al. Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology 2005; 114: 531-541.
Steinhoff M, Brzoska T, Luger TA. Keratinocytes in epidermal immune responses. Curr Opin Allergy Clin Immunol 2001; 1: 469-476.
Sanford JA, Gallo RL. Functions of the skin microbiota in health and disease. Semin Immunol 2013; 25: 370-377.
Malynn BA, Ma A. A20: A multifunctional tool for regulating immunity and preventing disease. Cell Immunol 2019; 340: 103914.
Das T, Chen Z, Hendriks RW, Kool M. A20/tumor necrosis factor alpha-induced protein 3 in immune cells controls development of autoinflammation and autoimmunity: lessons from mouse models. Front Immunol 2018; 9: 104.
Catrysse L, Vereecke L, Beyaert R, van Loo G. A20 in inflammation and autoimmunity. Trends Immunol 2014; 35: 22-31.
Stuart PE, Nair RP, Tsoi LC, Tejasvi T, Das S, Kang HM, et al. Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet 2015; 97: 816-836.
Dieguez-Gonzalez R, Calaza M, Perez-Pampin E, Balsa A, Blanco FJ, Canete JD, et al. Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-kappaB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility. Arthritis Res Ther 2009; 11: R42.
Kawasaki A, Ito S, Furukawa H, Hayashi T, Goto D, Matsumoto I, et al. Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study. Arthritis Res Ther 2010; 12: R174.
Perga S, Martire S, Montarolo F, Navone ND, Calvo A, Fuda G, et al. A20 in multiple sclerosis and Parkinson's disease: clue to a common dysregulation of anti-inflammatory pathways? Neurotox Res 2017; 32: 1-7.
Celli A, Sanchez S, Behne M, Hazlett T, Gratton E, Mauro T. The epidermal Ca(2+) gradient: measurement using the phasor representation of fluorescent lifetime imaging. Biophys J 2010; 98: 911-921.
Sours-Brothers S, Ma R, Koulen P. Ca2+-sensitive transcriptional regulation: direct DNA interaction by DREAM. Front Biosci (Landmark Ed) 2009; 14: 1851-1856.
Devos M, Mogilenko DA, Fleury S, Gilbert B, Becquart C, Quemener S, et al. Keratinocyte expression of A20/TNFAIP3 controls skin inflammation associated with atopic dermatitis and psoriasis. J Invest Dermatol 2019; 139: 135-145.
Fitz-Gibbon S, Tomida S, Chiu BH, Nguyen L, Du C, Liu M, et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 2013; 133: 2152-2160.
Dagnelie MA, Corvec S, Saint-Jean M, Nguyen JM, Khammari A, Dreno B. Cutibacterium acnes phylotypes diversity loss: a trigger for skin inflammatory process. J Eur Acad Dermatol Venereol 2019; 33: 2340-2348.
Jasson F, Nagy I, Knol AC, Zuliani T, Khammari A, Dreno B. Different strains of propionibacterium acnes modulate differently the cutaneous innate immunity. Exp Dermatol 2013; 22: 587-592.
Dreno B, Pecastaings S, Corvec S, Veraldi S, Khammari A, Roques C. Cutibacterium acnes (Propionibacterium acnes) and acne vulgaris: a brief look at the latest updates. J Eur Acad Dermatol Venereol 2018; 32 Suppl 2: 5-14.
Erdei L, Bolla BS, Bozo R, Tax G, Urban E, Kemeny L, et al. TNIP1 regulates cutibacterium acnes-induced innate immune functions in epidermal keratinocytes. Front Immunol 2018; 9: 2155.
Hu J, Wang G, Liu X, Zhou L, Jiang M, Yang L. A20 is critical for the induction of Pam3CSK4-tolerance in monocytic THP-1 cells. PLoS One 2014; 9: e87528.
Lippens S, Lefebvre S, Gilbert B, Sze M, Devos M, Verhelst K, et al. Keratinocyte-specific ablation of the NF-kappaB regulatory protein A20 (TNFAIP3) reveals a role in the control of epidermal homeostasis. Cell Death Differ 2011; 18: 1845-1853.
Dreno B. Bacteriological resistance in acne: a call to action. Eur J Dermatol 2016; 26: 127-132.
Orfanos CE, Zouboulis CC. Oral retinoids in the treatment of seborrhoea and acne. Dermatology 1998; 196: 140-147.
How to Cite
Copyright (c) 2021 Lilla Erdei, Beáta Szilvia Bolla, Renáta Bozó, Gábor Tax, Edit Urbán, Katalin Burián, Lajos Kemény, Kornélia Szabó
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All digitalized ActaDV contents is available freely online. The Society for Publication of Acta Dermato-Venereologica owns the copyright for all material published until volume 88 (2008) and as from volume 89 (2009) the journal has been published fully Open Access, meaning the authors retain copyright to their work.
Unless otherwise specified, all Open Access articles are published under CC-BY-NC licences, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for non-commercial purposes, provided proper attribution to the original work.