Advertisement
Journal of Investigative Dermatology Home

NF-κB1 contributes to imiquimod-induced psoriasis-like skin inflammation by inducing Vγ4+Vδ4+γδT17 cells

Published:November 11, 2021DOI:https://doi.org/10.1016/j.jid.2021.11.004

      Abstract

      Recent studies have identified nuclear factor kappa B (NF-κB)1 as a new disease susceptibility gene for psoriasis. Although accumulating evidence has demonstrated the importance of NF-κB signaling in various cell types in the pathogenesis of psoriasis, it remains unclear how NF-κB1 contributes to the pathogenesis of psoriasis. Here, we examined psoriasis-like skin diseases induced by topical administration of imiquimod (IMQ) in NF-κB1-deficient (NF-κB1-/-) mice and littermate wild-type (WT) mice. Compared to WT mice, NF-κB1-/- mice exhibited attenuated skin inflammation. The numbers of Vγ4+Vδ4+γδT17 cells, which cause skin inflammation in this model, were significantly reduced in the skin and draining lymph nodes in IMQ-treated NF-κB1-/- mice. NF-κB1 is preferentially phosphorylated in Vγ4+Vδ4+γδT17 cells in WT mice. In vitro proliferation of Vγ4+Vδ4+γδT17 cells but not conventional CD4+ T cells was significantly impaired in NF-κB1-/- mice compared to WT mice. RNA-sequencing analyses revealed that the expression of E2 factor (E2F) target genes was decreased in Vγ4+Vδ4+γδT cells by the absence of NF-κB1. Consistently, the cell cycle progression of Vγ4+Vδ4+γδT cells was reduced in NF-κB1-/- mice compared to WT mice. These results suggest that NF-κB1 plays a crucial role in the pathogenesis of IMQ-induced psoriasis-like skin inflammation by promoting the proliferation of Vγ4+Vδ4+γδT17 cells.

      Abbreviations:

      NF-κB (nuclear factor kappa B), IMQ (imiquimod), WT (wild-type), E2F (E2 factor), TH (T helper), Rel (v-rel avian reticuloendotheliosis viral oncogene homolog), MAP (mitogen-activated protein), PASI (psoriasis area severity index), ILC3s (group 3 innate lymphoid cells), LNs (lymph nodes), DETCs (dendritic epidermal T cells), ROR (retinoic acid receptor-related orphan receptor), GSEA (gene set enrichment analysis), wPGSA (weighted parametric gene set analysis), CDK (cyclin-dependent kinase), IKK (IκB kinase)
      To read this article in full you will need to make a payment
      Purchase one-time access
      Society Members (SID/ESDR), remember to log in for access.
      Subscribe to Journal of Investigative Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Akitsu A.
        • Iwakura Y.
        Interleukin-17-producing γδ T (γδ17) cells in inflammatory disease.
        Immunology. 2018; 155: 418-426
        • An Y.
        • Zhang J.
        • Cheng X.
        • Li B.
        • Tian Y.
        • Zhang X.
        • et al.
        miR-454 suppresses the proliferation and invasion of ovarian cancer by targeting E2F6.
        Cancer Cell Int. 2020; 20: 237
        • Armstrong A.W.
        • Read C.
        Pathophysiology, clinical presentation, and treatment of psoriasis: A Review.
        JAMA. 2020; 323: 1945-1960
        • Bachelez H.
        • van de Kerkhof P.C.
        • Strohal R.
        • Kubanov A.
        • Valenzuela F.
        • Lee J.H.
        • et al.
        Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.
        Lancet. 2015; 386: 552-561
        • Cai Y.
        • Shen X.
        • Ding C.
        • Qi C.
        • Li K.
        • Jala V.R.
        • et al.
        Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation.
        Immunity. 2011; 35: 596-610
        • Cao S.
        • Zhang X.
        • Edwards J.P.
        • Mosser D.M.
        NF-κB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages.
        J Biol Chem. 2006; 281: 26041-26050
        • Cartwright T.
        • Perkins N.D.
        • Willson C.L.
        NFκB1: a suppressor of inflammation, aging and cancer.
        FEBS J. 2016; 283: 1812-1822
        • Castillo-Gonzalez R.
        • Cibrian D.
        • Sanchez-Madrid F.
        Dissecting the complexity of γδ T-cell subsets in skin homeostasis, inflammation, and malignancy.
        J Allergy Clin Immunol. 2021; 147: 2030-2042
        • Chen L.
        • Li J.
        • Zhu W.
        • Kuang Y.
        • Liu T.
        • Zhang W.
        • et al.
        Skin and gut microbiome in psoriasis: Gaining insight into the pathophysiology of it and finding novel therapeutic strategies.
        Front Microbiol. 2020; 11: 589726
        • Chien Y.
        • Meyer C.
        • Bonneville M.
        γδ T cells: first line of defense and beyond.
        Annu Rev Immunol. 2014; 32: 121-155
        • Cho M.
        • Kang J.
        • Moon Y.
        • Nam H.
        • Jhun J.
        • Heo S.
        • et al.
        STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice.
        J Immunol. 2006; 176: 5652-5661
        • Dainichi T.
        • Kitoh A.
        • Otsuka A.
        • Nakajima S.
        • Nomura T.
        • Kaplan D.H.
        • et al.
        The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis.
        Nature Immunol. 2018; 19: 1286-1298
        • Dainichi T.
        • Matsumoto R.
        • Mostafa A.
        • Kabashima K.
        Immune control by TRAF6-mediated pathways of epithelial cells in the EIME (epithelial immune microenvironment).
        Front Immunol. 2019; 10: 1107
        • Ellinghaus D.
        • Jostins L.
        • Spain S.L.
        • Cortes A.
        • Bethune J.
        • Han B.
        • et al.
        Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
        Nat Genet. 2016; 48: 510-518
        • Garneau H.
        • Paquin M.C.
        • Carrier J.C.
        • Rivard N.
        E2F4 expression is required for cell cycle progression of normal intestinal crypt cells and colorectal cancer cells.
        J Cell Physiol. 2009; 221: 350-358
        • Garzorz-Stark N.
        • Lauffer F.
        • Krause L.
        • Thomas J.
        • Athenhan A.
        • Franz R.
        • et al.
        Toll-like receptor 7/8 agonists stimulate plasmacytoid dendritic cells to initiate TH17-deviated acute contact dermatitis in human subjects.
        J Allergy Clin Immunol. 2018; 141 (1320-33.e11)
        • Gray E.E.
        • Ramirez-Valle F.
        • Xu Y.
        • Wu S.
        • Wu Z.
        • Karjalainen K.E.
        • et al.
        Deficiency in IL-17-committed Vγ+ γδ T cells in a spontaneous Sox13-mutant CD45.1+ congenic mouse substrain provides protection from dermatitis.
        Nat Immunol. 2013; 14: 584-592
        • Grinberg-Bleyer Y.
        • Dainichi T.
        • Oh H.
        • Heise N.
        • Klein U.
        • Schmid R.M.
        • et al.
        NF-κB p65 and c-Rel control epidermal development and immune homeostasis in the skin.
        J Immunol. 2015; 194: 2472-2476
        • Hartwig T.
        • Pantelyushin S.
        • Croxford A.L.
        • Kulig P.
        • Becher B.
        Dermal IL-17-producing γδT cells establish long-lived memory in the skin.
        Eur J Immunol. 2015; 45: 3022-3033
        • 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
        • Hayden M.S.
        • Ghosh S.
        NF-κB, the first quarter-century: remarkable progress and outstanding questions.
        Genes Dev. 2012; 26: 203-234
        • Hayden M.S.
        • Ghosh S.
        Shared principles in NF-κB signaling.
        Cell. 2008; 132: 344-362
        • Hsu J.
        • Arand J.
        • Chaikovsky A.
        • Mooney N.A.
        • Demeter J.
        • Brison C.M.
        • et al.
        E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family.
        Nat Commun. 2019; 10: 2939
        • Hsu J.
        • Sage J.
        Novel functions for the transcription factor E2F4 in development and disease.
        Cell Cycle. 2016; 15: 3183-3190
        • Ishikawa H.
        • Claudio E.
        • Dambach D.
        • Raventos-Suarez C.
        • Ryan C.
        • Bravo R.
        Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor (NF-κB1) but expressing p50.
        J Exp Med. 1998; 187: 985-996
        • Kawakami E.
        • Nakaoka S.
        • Ohta T.
        • Kitano H.
        Weighted enrichment method for prediction of transcription regulators from transcriptome and global chromatin immunoprecipitation data.
        Nucleic Acids Res. 2016; 44: 5010-5021
        • Kent L.N.
        • Leone G.
        The broken cycle: E2F dysfunction in cancer.
        Nat Rev Cancer. 2019; 19: 326-338
        • Laggner U.
        • Meglio P.D.
        • Perepa G.K.
        • Hundhausen C.
        • Lacy K.E.
        • Ali N.
        • et al.
        Identification of a novel pro-inflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis.
        J Immunol. 2011; 187: 2783-2793
        • Li Q.
        • Verma I.M.
        NF-κB regulation in the immune system.
        Nat Rev Immunol. 2002; 2: 725-734
        • Liberzon A.
        • Birger C.
        • Thorvaldsdóttir H.
        • Ghandi M.
        • Mesirov J.P.
        • Tamayo P.
        The Molecular Signatures Database (MSigDB) hallmark gene set collection.
        Cell Syst. 2015; 1: 417-425
        • Lowes M.A.
        • Suárez-Fariñas M.
        • Krueger J.G.
        Immunology of psoriasis.
        Annu Rev Immunol. 2014; 32: 227-255
        • Matos T.R.
        • O'Malley J.T.
        • Lowry E.L.
        • Hamm D.
        • Kirsch I.R.
        • Robins H.S.
        • et al.
        Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones.
        J Clin Invest. 2017; 127: 4031-4041
        • McKenzie D.R.
        • Kara E.E.
        • Bastow C.R.
        • Tyllis T.S.
        • Fenix K.A.
        • Gregor C.E.
        • et al.
        IL-17-producing γδ T cells switch migratory patterns between resting and activated states.
        Nat Commun. 2017; 8: 15632
        • McKenzie D.R.
        • Comerford I.
        • Silva-Santos B.
        • McColl S.R.
        The emerging complexity of γδT17 cells.
        Front Immunol. 2018; 9: 796
      1. Mitchell S, Vargas J, Hoffmann A. Signaling via the NF-κB system. Wiley Interdiscip Rev Syst Biol Med 2016;8:227-241.

        • Moos S.
        • Mohebiany A.N.
        • Waisman A.
        • Kurschus F.C.
        Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes.
        J Invest Dermatol. 2019; 139: 1110-1117
        • Nikamo P.
        • Lysell J.
        • Stahle M.
        Association with genetic variants in the IL-23 and NF-κB pathways discriminates between mild and severe psoriasis skin disease.
        J Invest Dermatol. 2015; 135: 1969-1976
        • Pantelyushin S.
        • Haak S.
        • Ingold B.
        • Kulig P.
        • Heppner F.L.
        • Navarini A.A.
        • et al.
        Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice.
        J Clin Invest. 2012; 122: 2252-2256
        • Ramirez-Valle F.
        • Gray E.E.
        • Cyster J.G.
        Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary Il-17-driven responses.
        Proc Natl Acad Sci USA. 2015; 112: 8046-8051
        • Rebholz B.
        • Haase I.
        • Eckelt B.
        • Paxian S.
        • Flaig M.J.
        • Ghoreschi K.
        • et al.
        Crosstalk between keratinocytes and adaptive immune cells in an IκBα protein-mediated inflammatory disease of the skin.
        Immunity. 2007; 27: 296-307
        • Ruan Q.
        • Kameswaran V.
        • Zhang Y.
        • Zheng S.
        • Sun J.
        • Wang J.
        • et al.
        The Th17 immune response is controlled by the Rel-RORγ-RORγT transcriptional axis.
        J Exp Med. 2011; 208: 2321-2333
        • Sagar
        • Pokrovskii M.
        • Herman J.S.
        • Naik S.
        • Sock E.
        • Zeis P.
        • et al.
        Deciphering the regulatory landscape of fetal and adult γδ T-cell development at single-cell resolution.
        EMBO J. 2020; 39e104159
        • Sakurai K.
        • Dainichi T.
        • Garcet S.
        • Tsuchiya S.
        • Yamamoto Y.
        • Kitoh A.
        • et al.
        Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis.
        J Allergy Clin Immunol. 2019; 144: 1036-1049
        • Sandrock I.
        • Reinhardt A.
        • Ravens S.
        • Binz C.
        • Wilharm A.
        • Martins J.
        • et al.
        Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing γδ T cells.
        J Exp Med. 2018; 215: 3006-3018
        • Sha W.C.
        • Liou H.C.
        • Tuomanen E.I.
        • Baltimore D.
        Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses.
        Cell. 1995; 80: 321-330
        • Sheng Y.
        • Jin X.
        • Xu J.
        • Gao J.
        • Du X.
        • Duan D.
        • et al.
        Sequencing-based approach identified three new susceptibility loci for psoriasis.
        Nat Commun. 2014; 5: 4331
        • van der Fits L.
        • Mourits S.
        • Voerman J.S.
        • Kant M.
        • Boon L.
        • Laman J.D.
        • et al.
        Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
        J Immunol. 2009; 182: 5836-5845
        • Veldhoen M.
        Interleukin 17 is a chief orchestrator of immunity.
        Nat Immunol. 2017; 18: 612-621
        • Villanova F.
        • Flutter B.
        • Tosi I.
        • Grys K.
        • Sreeneebus H.
        • Perera G.K.
        • et al.
        Characterization of innate lymphoid cells (ILC) in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis.
        J Invest Dermatol. 2014; 134: 984-991
        • Yang R.
        • Wang M.
        • Zhang G.
        • Bao Y.
        • Wu Y.
        • Li X.
        • et al.
        E2F7-EZH2 axis regulates PTEN/AKT/mTOR signaling and glioblastoma progression.
        Br J Cancer. 2020; 123: 1445-1455
        • Works M.G.
        • Yin F.
        • Yin C.C.
        • Yiu Y.
        • Shew K.
        • Tran T.T.
        • et al.
        Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis.
        J Immunol. 2014; 193: 3278-3287
        • Zákostelská Z.
        • Málková J.
        • Klimešová K.
        • Rossmann P.
        • Hornová M.
        • Novosádová I.
        • et al.
        Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response.
        PLoS One. 2016; 11e0159539
        • Zeng X.
        • Meyer C.
        • Huang J.
        • Newell E.W.
        • Kidd B.A.
        • Wei Y.L.
        • et al.
        γδ T cells recognize haptens and mount a hapten-specific response.
        Elife. 2014; 3e03609
        • Zeng X.
        • Wei Y.
        • Huang J.
        • Newell E.W.
        • Yu H.
        • Kidd B.A.
        • et al.
        γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen specific interleukin 17 response.
        Immunity. 2012; 37: 524-534
        • Zhang Q.
        • Lenardo M.J.
        • Baltimore D.
        30 years of NFκB: A blossoming of relevance to human pathobiology.
        Cell. 2017; 168: 37-44
        • Zhu H.
        • Lou F.
        • Yin Q.
        • Gao Y.
        • Sun Y.
        • Bai J.
        • et al.
        RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease.
        EMBO Mol Med. 2017; 9: 589-604