Advertisement

Comparison of transcriptomic profiles in edge to center of plaque reveals chronological molecular events in psoriatic plaque formation

      Highlights

      • RNA-seq of the edge and the center of psoriatic plaques was performed.
      • Chronological plaque development was explained using RNA-seq data.
      • Edge of plaques shows high inflammatory activity and initiates plaque formation.
      • Center of plaques shows high growth activity and maintains the plaque.
      • Growth factors might diminish the inflammation in the center.

      Abstract

      Background

      Peripheral edge (PE) of plaques contains inflammatory molecules and has potential to initiate plaque formation, while the center (CE) of plaques has regression trends.

      Objective

      To elucidate the chronological molecular events by comparing the gene profiles in PE skin to those in CE skin.

      Methods

      Biopsied PE, CE, and uninvolved (UN) skin samples were analyzed by next-generation sequencing. Three groups of differentially expressed genes (DEGs) were analyzed, PE/UN-, CE/UN-, and PE/CE-skin-derived DEGs.

      Results

      PE skin contained inflammation-priming molecules, such as S100A7 and S100A15, and inflammatory drivers, such as interleukin (IL)-36α. IL-6 signaling was more active in PE than in CE skin. IL-8, S100A7, S100A8, S100A9, and human β-defensin-2 were all regulated with the similar pattern in both areas. However, PE skin created a more active inflammatory network and downstream functions, including chemotaxis and angiogenesis, were more prominent than in CE skin. Conversely, CE skin, where epidermal growth factor and hepatocyte growth factor increased their activity, was found to be more stable.

      Conclusion

      This is the first RNA-seq-based report to determine the chronological molecular events in plaque formation. In the early phase, inflammation might be initiated through molecules, such as IL-36α, S100A7, and S100A15, as observed in PE skin. The inflammation state in PE skin progresses to the more stable state found in CE skin. In CE skin, the growth factor activities are increased, which might lead to attenuation of initial inflammation and initiation of the regression phase. These molecular events may accelerate research towards developing novel therapies for psoriasis.

      Abbreviations:

      CE skin (center of lesional skin), PE skin (peripheral edge of lesional skin), UN skin (uninvolved skin)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Griffiths C.E.M.
        • Armstrong A.W.
        • Gudjonsson J.E.
        • Barker J.
        Psoriasis.
        Lancet. 2021; 397: 1301-1315
        • Kamiya K.
        • Kishimoto M.
        • Sugai J.
        • Komine M.
        • Ohtsuki M.
        Risk factors for the development of psoriasis.
        Int J. Mol. Sci. 2019; 20
        • Greb J.E.
        • Goldminz A.M.
        • Elder J.T.
        • Lebwohl M.G.
        • Gladman D.D.
        • Wu J.J.
        • et al.
        Psoriasis.
        Nat. Rev. Dis. Prim. 2016; 2: 16082
        • Armstrong A.W.
        • Read C.
        Pathophysiology, clinical presentation, and treatment of psoriasis: a review.
        Jama. 2020; 323: 1945-1960
        • Hawkes J.E.
        • Chan T.C.
        • Krueger J.G.
        Psoriasis pathogenesis and the development of novel targeted immune therapies.
        J. Allergy Clin. Immunol. 2017; 140: 645-653
        • Yamanaka K.
        • Yamamoto O.
        • Honda T.
        Pathophysiology of psoriasis: A review.
        J. Dermatol. 2021; 48: 722-731
        • Tsuda H.
        • Thummakriengkrai J.
        • Meephansan J.
        • Wongpiyaboborn J.
        • Phadungsaksawasdi P.
        • Vacharanukrauh P.
        • et al.
        Meephansan J. The JAK-STAT Signaling Pathway in Chronic Inflammatory Skin Disease. Thammasat University Press Tha Prachan, Thailand2021: 95-144
        • Kim J.
        • Lee J.
        • Kim H.J.
        • Kameyama N.
        • Nazarian R.
        • Der E.
        • et al.
        Single-cell transcriptomics applied to emigrating cells from psoriasis elucidate pathogenic versus regulatory immune cell subsets.
        J. Allergy Clin. Immunol. 2021; 148: 1281-1292
        • Boonpethkaew S.
        • Meephansan J.
        • Jumlongpim O.
        • Tangtanatakul P.
        • Soonthornchai W.
        • Wongpiyabovorn J.
        • et al.
        Transcriptomic Profiling of Peripheral Edge of Lesions to Elucidate the Pathogenesis of Psoriasis Vulgaris.
        Int. J. Mol. Sci. 2022; 23: 4983
        • Komine M.
        • Karakawa M.
        • Takekoshi T.
        • Sakurai N.
        • Minatani Y.
        • Mitsui H.
        • et al.
        Early inflammatory changes in the "perilesional skin" of psoriatic plaques: is there interaction between dendritic cells and keratinocytes?.
        J. Invest Dermatol. 2007; 127: 1915-1922
        • Ringham L.
        • Prusinkiewicz P.
        • Gniadecki R.
        Skin patterning in psoriasis by spatial interactions between pathogenic.
        Cytokines, Isc. 2019; 20: 546-553
        • Jabbari A.
        • Suárez-Fariñas M.
        • Dewell S.
        • Krueger J.G.
        Transcriptional profiling of psoriasis using RNA-seq reveals previously unidentified differentially expressed genes.
        J. Invest Dermatol. 2012; 132: 246-249
        • Vacharanukrauh P.
        • Meephansan J.
        • Ponnikorn S.
        • Tangtanatakul P.
        • Soonthornchai W.
        • Wongpiyabovorn J.
        • et al.
        Transcriptome profiling in psoriasis: NB-UVB treatment-associated transcriptional changes and modulation of autoinflammation in perilesional skin in early-phase disease.
        J. Dermatol. Sci. 2022;
        • Loraine A.E.
        • Blakley I.C.
        • Jagadeesan S.
        • Harper J.
        • Miller G.
        • Firon N.
        Analysis and Visualization of RNA-Seq Expression Data Using RStudio, Bioconductor, and Integrated Genome Browser.
        in: Alonso J.M. Stepanova A.N. Plant Functional Genomics: Methods and Protocols. Springer New York, New York, NY2015: 481-501
        • Schmittgen T.D.
        • Livak K.J.
        Analyzing real-time PCR data by the comparative C(T) method.
        Nat. Protoc. 2008; 3: 1101-1108
        • Morizane S.
        • Gallo R.L.
        Antimicrobial peptides in the pathogenesis of psoriasis.
        J. Dermatol. 2012; 39: 225-230
        • Johnston A.
        • Xing X.
        • Guzman A.M.
        • Riblett M.
        • Loyd C.M.
        • Ward N.L.
        • et al.
        IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression.
        J. Immunol. 2011; 186: 2613-2622
        • Furue M.
        • Furue K.
        • Tsuji G.
        • Nakahara T.
        Interleukin-17A and Keratinocytes in Psoriasis.
        Int J. Mol. Sci. 2020; 21
        • Keermann M.
        • Kõks S.
        • Reimann E.
        • Abram K.
        • Erm T.
        • Silm H.
        • et al.
        Expression of IL-36 family cytokines and IL-37 but not IL-38 is altered in psoriatic skin.
        J. Dermatol. Sci. 2015; 80: 150-152
        • Furue K.
        • Ito T.
        • Tanaka Y.
        • Yumine A.
        • Hashimoto-Hachiya A.
        • Takemura M.
        • et al.
        Cyto/chemokine profile of in vitro scratched keratinocyte model: Implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon.
        J. Dermatol. Sci. 2019; 94: 244-251
        • Jiang Z.
        • Liu Y.
        • Li C.
        • Chang L.
        • Wang W.
        • Wang Z.
        • et al.
        IL-36γ Induced by the TLR3-SLUG-VDR Axis Promotes Wound Healing via REG3A.
        J. Invest Dermatol. 2017; 137: 2620-2629
        • Boutet M.A.
        • Bart G.
        • Penhoat M.
        • Amiaud J.
        • Brulin B.
        • Charrier C.
        • et al.
        Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease.
        Clin. Exp. Immunol. 2016; 184: 159-173
        • Carrier Y.
        • Ma H.L.
        • Ramon H.E.
        • Napierata L.
        • Small C.
        • O'Toole M.
        • et al.
        Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis.
        J. Invest Dermatol. 2011; 131: 2428-2437
        • Müller A.
        • Hennig A.
        • Lorscheid S.
        • Grondona P.
        • Schulze-Osthoff K.
        • Hailfinger S.
        • et al.
        IκBζ is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes.
        Proc. Natl. Acad. Sci. USA. 2018; 115: 10088-10093
        • Foster A.M.
        • Baliwag J.
        • Chen C.S.
        • Guzman A.M.
        • Stoll S.W.
        • Gudjonsson J.E.
        • et al.
        IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.
        J. Immunol. 2014; 192: 6053-6061
        • Hegyi Z.
        • Zwicker S.
        • Bureik D.
        • Peric M.
        • Koglin S.
        • Batycka-Baran A.
        • et al.
        Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 "alarmins" psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis.
        J. Invest Dermatol. 2012; 132: 1416-1424
        • Christmann C.
        • Zenker S.
        • Martens L.
        • Hübner J.
        • Loser K.
        • Vogl T.
        • et al.
        Interleukin 17 Promotes Expression of Alarmins S100A8 and S100A9 During the Inflammatory Response of Keratinocytes.
        Front Immunol. 2020; 11599947
        • Lee Y.
        • Jang S.
        • Min J.K.
        • Lee K.
        • Sohn K.C.
        • Lim J.S.
        • et al.
        S100A8 and S100A9 are messengers in the crosstalk between epidermis and dermis modulating a psoriatic milieu in human skin.
        Biochem Biophys. Res Commun. 2012; 423: 647-653
        • Chimenti M.S.
        • Triggianese P.
        • Botti E.
        • Narcisi A.
        • Conigliaro P.
        • Giunta A.
        • et al.
        S100A8/A9 in psoriatic plaques from patients with psoriatic arthritis.
        J. Int Med Res. 2016; 44: 33-37
        • Wolf R.
        • Mascia F.
        • Dharamsi A.
        • Howard O.M.
        • Cataisson C.
        • Bliskovski V.
        • et al.
        Gene from a psoriasis susceptibility locus primes the skin for inflammation.
        Sci. Transl. Med. 2010; 2: 61ra90
        • Wang S.
        • Zhang Z.
        • Peng H.
        • Zeng K.
        Recent advances on the roles of epidermal growth factor receptor in psoriasis.
        Am. J. Transl. Res. 2019; 11: 520-528
        • Pastore S.
        • Mascia F.
        • Mariani V.
        • Girolomoni G.
        The epidermal growth factor receptor system in skin repair and inflammation.
        J. Invest Dermatol. 2008; 128: 1365-1374
        • Maretzky T.
        • Evers A.
        • Zhou W.
        • Swendeman S.L.
        • Wong P.M.
        • Rafii S.
        • et al.
        Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17.
        Nat. Commun. 2011; 2: 229
        • Nakai K.
        • Yoneda K.
        • Moriue T.
        • Igarashi J.
        • Kosaka H.
        • Kubota Y.
        HB-EGF-induced VEGF production and eNOS activation depend on both PI3 kinase and MAP kinase in HaCaT cells.
        J. Dermatol. Sci. 2009; 55: 170-178
        • Franzke C.W.
        • Cobzaru C.
        • Triantafyllopoulou A.
        • Löffek S.
        • Horiuchi K.
        • Threadgill D.W.
        • et al.
        Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation.
        J. Exp. Med. 2012; 209: 1105-1119
        • Zhang Z.
        • Xiao C.
        • Gibson A.M.
        • Bass S.A.
        • Khurana G.K.
        Hershey, EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis.
        J. Immunol. 2014; 192: 859-866
        • Czyz M.
        HGF/c-MET signaling in melanocytes and melanoma.
        Int J. Mol. Sci. 2018; 19
        • Nakamura T.
        • Mizuno S.
        The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine.
        Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 2010; 86: 588-610
        • Schmitt S.
        • Safferling K.
        • Westphal K.
        • Hrabowski M.
        • Müller U.
        • Angel P.
        • et al.
        Stathmin regulates keratinocyte proliferation and migration during cutaneous regeneration.
        PLoS One. 2013; 8e75075
        • Hisadome M.
        • Ohnishi T.
        • Kakimoto K.
        • Kusuyama J.
        • Bandow K.
        • Kanekura T.
        • et al.
        Hepatocyte growth factor reduces CXCL10 expression in keratinocytes.
        FEBS Lett. 2016; 590: 3595-3605
        • Meng H.
        • Wei F.
        • Zhou Y.
        • Hu L.
        • Ge Z.
        • Jin J.
        • et al.
        Overexpression of Hepatocyte Growth Factor in Dental Pulp Stem Cells Ameliorates the Severity of Psoriasis by Reducing Inflammatory Responses.
        Stem Cells Dev. 2021; 30: 876-889
        • Malinina A.
        • Dikeman D.
        • Westbrook R.
        • Moats M.
        • Gidner S.
        • Poonyagariyagorn H.
        • et al.
        IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung.
        Aging Cell. 2020; 19e13130
        • Ikeyama S.
        • Wang X.T.
        • Li J.
        • Podlutsky A.
        • Martindale J.L.
        • Kokkonen G.
        • et al.
        Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury.
        J. Biol. Chem. 2003; 278: 16726-16731
        • Gerritsen M.E.
        • Tomlinson J.E.
        • Zlot C.
        • Ziman M.
        • Hwang S.
        Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells.
        Br. J. Pharm. 2003; 140: 595-610
        • Gao H.
        • Schwartz R.C.
        C/EBPzeta (CHOP/Gadd153) is a negative regulator of LPS-induced IL-6 expression in B cells.
        Mol. Immunol. 47(. 2009; : 390-397
        • Thevenot P.T.
        • Sierra R.A.
        • Raber P.L.
        • Al-Khami A.A.
        • Trillo-Tinoco J.
        • Zarreii P.
        • et al.
        The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors.
        Immunity. 2014; 41: 389-401
        • Wu W.
        • Dietze K.K.
        • Gibbert K.
        • Lang K.S.
        • Trilling M.
        • Yan H.
        • et al.
        TLR ligand induced IL-6 counter-regulates the anti-viral CD8(+) T cell response during an acute retrovirus infection.
        Sci. Rep. 2015; 5: 10501
        • Cifaldi L.
        • Prencipe G.
        • Caiello I.
        • Bracaglia C.
        • Locatelli F.
        • De Benedetti F.
        • et al.
        Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome.
        Arthritis Rheuma. 2015; 67: 3037-3046
        • Wang X.
        • Sun R.
        • Hao X.
        • Lian Z.X.
        • Wei H.
        • Tian Z.
        IL-17 constrains natural killer cell activity by restraining IL-15-driven cell maturation via SOCS3.
        Proc. Natl. Acad. Sci. USA. 2019; 116: 17409-17418
        • Batista M.D.
        • Ho E.L.
        • Kuebler P.J.
        • Milush J.M.
        • Lanier L.L.
        • Kallas E.G.
        • et al.
        Skewed distribution of natural killer cells in psoriasis skin lesions.
        Exp. Dermatol. 2013; 22: 64-66