Uncoupling melanogenesis from proliferation in epidermal melanocytes responding to stimulation with psoriasis-related proinflammatory cytokines

Published:December 14, 2022DOI:


      • Increased IL8-CXCR2 signaling induces melanocyte proliferation in psoriatic plaques.
      • Increased β-defensin 3 expression suppresses melanin synthesis in psoriatic plaques.
      • Stimulation of TNFα/IL17A on melanocytes proliferation, but rather on melanogenesis.



      Few studies have addressed the impact of the psoriasis-related proinflammatory cytokines on the proliferation and melanogenesis of melanocytes (MCs) in lesional psoriatic skin.


      We investigated the effects of TNFα, IL17A, and IL8 on the proliferation and melanin synthesis of MCs.


      Skin specimens were biopsied from patients with psoriasis vulgaris at the active stage, or from the tail skin of Dct-LacZ mice with imiquimod (IMQ)-induced psoriasiform dermatitis. Cultured keratinocytes (KCs), MCs, and human skin explants were used in this study. The numbers of MCs were measured via β-galactosidase staining, EdU incorporation and HMB45 immunohistochemical staining. The expression of human β-defensin 3 (hBD3) in KCs was silenced by siRNA, the conditioned medium (CM) from siRNA-transfected KCs was used to treat MCs, then followed by αMSH stimulation. The melanogenesis-related genes were examined by using qRT-PCR and western blotting.


      The increased number of MCs and decreased melanin content were highly relevant to the enhanced expression of IL8 and BD3 both in human psoriatic skin and in IMQ-treated mouse tail skin. IL8 expression in KCs and CXCR2 expression in MCs was significantly increased by IL17A and TNFα, the αMSH-induced upregulations of microphthalmia-associated transcription factor (MITF) and tyrosinase in MCs were abrogated by the CM from hBD3-unsilenced KCs, but not from hBD3-silenced KCs.


      Our results suggest the roles of IL8-CXCR2 activation in promoting MC proliferation and of BD3 upregulation in reducing melanogenesis. These findings have been implicated in the underlying mechanism that active psoriasis prefers hypopigmentation despite chronic inflammation.


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        • Greb J.E.
        • Goldminz A.M.
        • Elder J.T.
        • Lebwohl M.G.
        • Gladman D.D.
        • Wu J.,J.
        • et al.
        Nat. Rev. Dis. Prim. 2016; 2: 16082
        • Sharma A.
        • Upadhyay D.K.
        • Gupta G.G.
        • Narang R.K.
        • Rai V.K.
        IL-23/Th17 axis: A potential therapeutic target of psoriasis.
        Curr. Drug Res. Rev. 2022; 14: 24-36
        • Cichorek M.
        • Wachulska M.
        • Stasiewicz A.
        • Tymińska A.
        Skin melanocytes: biology and development.
        Post. Dermatol. Alergol. 2013; 30: 30-41
        • Nordlund J.J.
        The melanocyte and the epidermal melanin unit: an expanded concept.
        Dermatol. Clin. 2007; 25: 271-281
        • Bellinato F.
        • Gisondi P.
        • Girolomoni G.
        Latest advances for the treatment of chronic plaque psoriasis with biologics and oral small molecules.
        Biologics. 2021; 15: 247-253
        • Matsunaga N.
        • Virador V.
        • Santis C.
        • Vieira W.D.
        • Furumura M.
        • Matsunaga J.
        • et al.
        In situ localization of agouti signal protein in murine skin using immunohistochemistry with an ASP-specific antibody.
        Biochem. Biophys. Res. Commun. 2000; 270: 176-182
        • Mackenzie M.A.
        • Jordan S.A.
        • Budd P.S.
        • Jackson I.J.
        Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo.
        Dev. Biol. 1997; 192: 99-107
        • Liao Z.K.
        • Hu S.H.
        • Han B.Y.
        • Qiu X.
        • Jiang S.
        • Lei T.C.
        Pro-pigmentary action of 5-fluorouracil through the stimulated secretion of CXCL12 by dermal fibroblasts.
        Chin. Med. J. (Engl. ). 2021; 134: 2475-2482
        • Hu Q.M.
        • Yi W.J.
        • Su M.Y.
        • Jiang S.
        • Xu S.Z.
        • Lei T.C.
        Induction of retinal-dependent calcium influx in human melanocytes by UVA or UVB radiation contributes to the stimulation of melanosome transfer.
        Cell Prolif. 2017; 50e12372
        • Romana-Souza B.
        • Silva-Xavier W.
        • Monte-Alto-Costa A.
        Topical retinol attenuates stress-induced ageing signs in human skin ex vivo, through EGFR activation via EGF, but not ERK and AP-1 activation.
        Exp. Dermatol. 2019; 28: 906-913
        • Neil J.E.
        • Brown M.B.
        • Williams A.C.
        Human skin explant model for the investigation of topical therapeutics.
        Sci. Rep. 2020; 10: 21192
        • Terazawa S.
        • Imokawa G.
        Signaling cascades activated by UVB in human melanocytes lead to the increased expression of melanocyte receptors, endothelin B receptor and c-KIT.
        Photochem. Photobiol. 2018; 94: 421-431
        • Kang H.Y.
        • Park T.J.
        • Jin S.H.
        Imiquimod, a Toll-like receptor 7 agonist, inhibits melanogenesis and proliferation of human melanocytes.
        J. Invest. Dermatol. 2009; 129: 243-246
        • Swope V.B.
        • Abdel-Malek Z.A.
        MC1R: Front and center in the bright side of dark eumelanin and DNA repair.
        Int J. Mol. Sci. 2018; 19: 2667
        • Le Pape E.
        • Passeron T.
        • Giubellino A.
        • Valencia J.C.
        • Wolber R.
        • Hearing V.J.
        Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r.
        Proc. Natl. Acad. Sci. USA. 2009; 106: 1802-1807
        • Swope V.B.
        • Jameson J.A.
        • McFarland K.L.
        • Supp D.M.
        • Miller W.E.
        • McGraw D.W.
        • et al.
        Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3.
        J. Invest Dermatol. 2012; 132: 2255-2262
        • Hinrichsen K.
        • Podschun R.
        • Schubert S.
        • Schröder J.M.
        • Harder J.
        • Proksch E.
        Mouse beta-defensin-14, an antimicrobial ortholog of human beta-defensin-3.
        Antimicrob. Agents Chemother. 2008; 52: 1876-1879
        • Bellinato F.
        • Gisondi P.
        • Girolomoni G.
        Latest advances for the treatment of chronic plaque psoriasis with biologics and oral small molecules.
        Biologics. 2021; 15: 247-253
        • Russo R.C.
        • Garcia C.C.
        • Teixeira M.M.
        • Amaral F.A.
        The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases.
        Expert Rev. Clin. Immunol. 2014; 10: 593-619
        • Heidemann J.
        • Ogawa H.
        • Dwinell M.B.
        • Rafiee P.
        • Maaser C.
        • Gockel H.R.
        • et al.
        Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2.
        J. Biol. Chem. 2003; 278: 8508-8515
        • Bento A.F.
        • Leite D.F.
        • Claudino R.F.
        • Hara D.B.
        • Leal P.C.
        • Calixto J.B.
        The selective nonpeptide CXCR2 antagonist SB225002 ameliorates acute experimental colitis in mice.
        J. Leukoc. Biol. 2008; 84: 1213-1221
        • Sriwiriyanont P.
        • Ohuchi A.
        • Hachiya A.
        • Visscher M.O.
        • Boissy R.E.
        Interaction between stem cell factor and endothelin-1: effects on melanogenesis in human skin xenografts.
        Lab. Invest. 2006; 86: 1115-1125
        • Wang Y.
        • Viennet C.
        • Robin S.
        • Berthon J.Y.
        • He L.
        • Humbert P.
        Precise role of dermal fibroblasts on melanocyte pigmentation.
        J. Dermatol. Sci. 2017; 88: 159-166
        • Montero-Vilchez T.
        • Soler-Góngora M.
        • Martínez-López A.
        • Ana F.G.
        • Buendía-Eisman A.
        • Molina-Leyva A.
        • et al.
        Epidermal barrier changes in patients with psoriasis: The role of phototherapy.
        Photodermatol. Photoimmunol. Photomed. 2021; 37: 285-292
        • Rothstein B.
        • Gottlieb A.
        Secukinumab for treating plaque psoriasis.
        Expert. Opin. Biol. Ther. 2016; 16: 119-128
        • Di Cesare A.
        • Fargnoli M.C.
        • Marinucci A.
        • Peris K.
        Rationale for the development of speckled hyperpigmentation in the areas of psoriatic plaques after treatment with biologic agents.
        J. Invest. Dermatol. 2015; 135: 318-320
        • Wang F.
        • Zhang X.
        • Xia P.
        • Zhang L.
        • Zhang Z.
        Enhancement of mRNA expression of survivin and human beta-defensin-3 in lesions of psoriasis vulgaris.
        Eur. J. Dermatol. 2016; 26: 28-33
        • García-Borrón J.C.
        • Abdel-Malek Z.
        • Jiménez-Cervantes C.
        MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation.
        Pigment Cell Melanoma Res. 2014; 27: 699-720
        • Hida T.
        • Wakamatsu K.
        • Sviderskaya E.V.
        • Donkin A.J.
        • Montoliu L.
        • Lynn M.
        Lamoreux, et al., Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway.
        Pigment Cell Melanoma Res. 2009; 22: 623-634
        • Sharquite K.E.
        • Noaimi A.A.
        • Noori N.Y.
        Imiquimod cream in low concentrations as new topical therapy for melasma.
        Am. J. Dermatol. Venereol. 2019; 8: 66-72
        • Arnott C.H.
        • Scott K.A.
        • Moore R.J.
        • Robinson S.C.
        • Thompson R.G.
        • Balkwill F.R.
        Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development.
        Oncogene. 2004; 23: 1902-1910
        • Singh M.
        • Mansuri M.S.
        • Kadam A.
        • Palit S.P.
        • Dwivedi M.
        • Laddha N.C.
        • et al.
        Tumor necrosis factor-alpha affects melanocyte survival and melanin synthesis via multiple pathways in vitiligo.
        Cytokine. 2021; 140155432
        • Taub A.
        • Bucay V.
        • Keller G.
        • Williams J.
        • Mehregan D.
        Multi-center, double-blind, vehicle-controlled clinical trial of an alpha and beta defensin-containing anti-aging skin care regimen with clinical, histopathologic, immunohistochemical, photographic, and ultrasound evaluation.
        J. Drugs Dermatol. 2018; 17: 426-441
        • Mockenhaupt M.
        • Peters F.
        • Schwenk-Davoine I.
        • Herouy Y.
        • Schraufstätter I.
        • et al.
        Evidence of involvement of CXC-chemokines in proliferation of cultivated human melanocytes.
        Int. J. Mol. Med. 2003; 12: 597-601
        • Lotti T.
        • Hercogova J.
        • Fabrizi G.
        G, Advances in the treatment options for vitiligo: activated low-dose cytokines-based therapy.
        Expert Opin. Pharmacother. 2015; 16: 2485-2496