Advertisement
Journal of Investigative Dermatology Home

RIP1-Mediated Necroptosis Facilitates Oxidative Stress‒Induced Melanocyte Death, Offering Insight into Vitiligo

  • Author Footnotes
    2 These authors contributed equally to this work.
    Bowei Li
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    2 These authors contributed equally to this work.
    Xiuli Yi
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    2 These authors contributed equally to this work.
    Tongtian Zhuang
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Shaolong Zhang
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Shuli Li
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Yuqi Yang
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Tingting Cui
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Jiaxi Chen
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Yuqian Chang
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    3 These authors contributed equally to this work.
    Tianwen Gao
    Footnotes
    3 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    3 These authors contributed equally to this work.
    Chunying Li
    Footnotes
    3 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    3 These authors contributed equally to this work.
    Ling Liu
    Correspondence
    Correspondence: Ling Liu, Department of Dermatology, Xijing hospital, Fourth Military Medical University, 127# Changle xi Road, Xi’an 710032, China.
    Footnotes
    3 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    2 These authors contributed equally to this work.
    3 These authors contributed equally to this work.
      Vitiligo is a common depigmentation disease characterized by melanocyte death, which is attributed to various mechanisms such as apoptosis and autoimmune destruction. However, whether necroptosis, a newly discovered way of cell death, plays a key role in the pathogenesis of vitiligo is still elusive and has not been well-studied. In this study, we found that necroptosis markers, including phosphorylated RIP3 and phosphorylated-MLKL, were positive in melanocytes from vitiligo perilesional skin, which supported the existence of necroptosis in vitiligo. Furthermore, the expression of RIP1 was remarkably upregulated in melanocytes treated with hydrogen peroxide. Then, RIP1 intervention suppression and MLKL deficiency could significantly enhance the resistance of melanocytes to hydrogen peroxide‒induced necroptosis. Mechanistically, we confirmed that RIP1 and RIP3 could form necrosomes under oxidative stress and further trigger phosphorylated MLKL translocation to the cell membrane, which led to the destruction of melanocytes. Finally, we showed that RIP1-mediated generation of mitochondrial ROS contributed to necrosome formation in melanocytes. Collectively, our study confirms that necroptosis significantly facilitates oxidative stress‒induced melanocyte death through the RIP1 signaling pathway, offering insight into vitiligo.

      Abbreviations:

      H2O2 (hydrogen peroxide), Nec-1 (necrostatin-1), NHM (normal human melanocyte), p-MLKL (phosphorylated MLKL), p-RIP3 (phosphorylated RIP3), shRNA (short hairpin RNA)
      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

        • Cai Z.
        • Jitkaew S.
        • Zhao J.
        • Chiang H.C.
        • Choksi S.
        • Liu J.
        • et al.
        Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis.
        Nat Cell Biol. 2014; 16: 200
        • Cho Y.S.
        • Challa S.
        • Moquin D.
        • Genga R.
        • Ray T.D.
        • Guildford M.
        • et al.
        Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation.
        Cell. 2009; 137: 1112-1123
        • Degterev A.
        • Huang Z.
        • Boyce M.
        • Li Y.
        • Jagtap P.
        • Mizushima N.
        • et al.
        Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury.
        Nat Chem Biol. 2005; 1: 234
        • Dell'Anna M.L.
        • Urbanelli S.
        • Mastrofrancesco A.
        • Camera E.
        • Iacovelli P.
        • Leone G.
        • et al.
        Alterations of mitochondria in peripheral blood mononuclear cells of vitiligo patients.
        Pigment Cell Res. 2003; 16: 553-559
        • Ding G.Z.
        • Zhao W.E.
        • Li X.
        • Gong Q.L.
        • Lu Y.
        A comparative study of mitochondrial ultrastructure in melanocytes from perilesional vitiligo skin and perilesional halo nevi skin.
        Arch Dermatol Res. 2015; 307: 281-289
        • Ding W.
        • Shang L.
        • Huang J.F.
        • Li N.
        • Chen D.
        • Xue L.X.
        • et al.
        Receptor interacting protein 3-induced RGC-5 cell necroptosis following oxygen glucose deprivation.
        BMC Neurosci. 2015; 16: 49
        • Frisoli M.L.
        • Harris J.E.
        Vitiligo: mechanistic insights lead to novel treatments.
        J Allergy Clin Immunol. 2017; 140: 654-662
        • Fuchs Y.
        • Steller H.
        Programmed cell death in animal development and disease.
        Cell. 2011; 147: 1640
        • Geserick P.
        • Wang J.
        • Schilling R.
        • Horn S.
        • Harris P.A.
        • Bertin J.
        • et al.
        Absence of RIPK3 predicts necroptosis resistance in malignant melanoma.
        Cell Death Dis. 2015; 6: e1884
        • Guo H.
        • Omoto S.
        • Harris P.A.
        • Finger J.N.
        • Bertin J.
        • Gough P.J.
        • et al.
        Herpes simplex virus suppresses necroptosis in human cells.
        Cell Host Microbe. 2015; 17: 243-251
        • Hawk M.A.
        • Gorsuch C.L.
        • Fagan P.
        • Lee C.
        • Kim S.E.
        • Hamann J.C.
        • et al.
        RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells.
        Nat Cell Biol. 2018; 20: 272-284
        • He Y.
        • Li S.
        • Zhang W.
        • Dai W.
        • Cui T.
        • Wang G.
        • et al.
        Dysregulated autophagy increased melanocyte sensitivity to H2O2-induced oxidative stress in vitiligo.
        Sci Rep. 2017; 7: 42394
        • Ito Y.
        • Ofengeim D.
        • Najafov A.
        • Das S.
        • Saberi S.
        • Li Y.
        • et al.
        RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS.
        Science. 2016; 353: 603-608
        • Jhun J.
        • Lee S.H.
        • Kim S.Y.
        • Ryu J.
        • Kwon J.Y.
        • Na H.S.
        • et al.
        RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis.
        J Transl Med. 2019; 17: 84
        • Jian Z.
        • Li K.
        • Song P.
        • Zhu G.
        • Zhu L.
        • Cui T.
        • et al.
        Impaired activation of the Nrf2-ARE signaling pathway undermines H2O2-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo.
        J Invest Dermatol. 2014; 134: 2221-2230
        • Kang P.
        • Zhang W.
        • Chen X.
        • Yi X.
        • Song P.
        • Chang Y.
        • et al.
        TRPM2 mediates mitochondria-dependent apoptosis of melanocytes under oxidative stress.
        Free Radic Biol Med. 2018; 126: 259-268
        • Kim J.H.
        • Choi T.G.
        • Park S.
        • Yun H.R.
        • Nguyen N.N.Y.
        • Jo Y.H.
        • et al.
        Mitochondrial ROS-derived PTEN oxidation activates PI3K pathway for mTOR-induced myogenic autophagy.
        Cell Death Differ. 2018; 25: 1921-1937
        • LaRocca T.J.
        • Sosunov S.A.
        • Shakerley N.L.
        • Ten V.S.
        • Ratner A.J.
        Hyperglycemic conditions prime cells for RIP1-dependent necroptosis.
        J Biol Chem. 2016; 291: 13753-13761
        • Le Poole I.C.
        • Boissy R.E.
        • Sarangarajan R.
        • Chen J.
        • Forristal J.J.
        • Sheth P.
        • et al.
        PIG3V, an immortalized human vitiligo melanocyte cell line, expresses dilated endoplasmic reticulum.
        In Vitro Cell Dev Biol Anim. 2000; 36: 309-319
        • Le Poole I.C.
        • van den Berg F.M.
        • van den Wijngaard R.M.
        • Galloway D.A.
        • van Amstel P.J.
        • Buffing A.A.
        • et al.
        Generation of a human melanocyte cell line by introduction of HPV16 E6 and E7 genes.
        In Vitro Cell Dev Biol Anim. 1997; 33: 42-49
        • Li D.
        • Xu T.
        • Cao Y.
        • Wang H.
        • Li L.
        • Chen S.
        • et al.
        A cytosolic heat shock protein 90 and cochaperone CDC37 complex is required for RIP3 activation during necroptosis.
        Proc Natl Acad Sci USA. 2015; 112: 5017-5022
        • Liu B.
        • Jian Z.
        • Li Q.
        • Li K.
        • Wang Z.
        • Liu L.
        • et al.
        Baicalein protects human melanocytes from H2O2-induced apoptosis via inhibiting mitochondria-dependent caspase activation and the p38 MAPK pathway.
        Free Radic Biol Med. 2012; 53: 183-193
        • Newton K.
        RIPK1 and RIPK3: critical regulators of inflammation and cell death.
        Trends Cell Biol. 2015; 25: 347-353
        • Ni R.
        • Cao T.
        • Xiong S.
        • Ma J.
        • Fan G.C.
        • Lacefield J.C.
        • et al.
        Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy.
        Free Radic Biol Med. 2016; 90: 12-23
        • Nikseresht S.
        • Khodagholi F.
        • Nategh M.
        • Dargahi L.
        RIP1 inhibition rescues from LPS-induced RIP3-mediated programmed cell death, distributed energy metabolism and spatial memory impairment.
        J Mol Neurosci. 2015; 57: 219-230
        • Ofengeim D.
        • Yuan J.
        Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death.
        Nat Rev Mol Cell Biol. 2013; 14: 727-736
        • Petrie E.J.
        • Czabotar P.E.
        • Murphy J.M.
        The structural basis of necroptotic cell death signaling.
        Trends Biochem Sci. 2019; 44: 53-63
        • Picardo M.
        • Dell'Anna M.L.
        • Ezzedine K.
        • Hamzavi I.
        • Harris J.E.
        • Parsad D.
        • et al.
        Vitiligo.
        Nat Rev Dis Primers. 2015; 1: 15011
        • Robinson N.
        • McComb S.
        • Mulligan R.
        • Dudani R.
        • Krishnan L.
        • Sad S.
        Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium.
        Nat Immunol. 2012; 13: 954-962
        • Rohde K.
        • Kleinesudeik L.
        • Roesler S.
        • Löwe O.
        • Heidler J.
        • Schröder K.
        • et al.
        A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis.
        Cell Death Differ. 2017; 24: 83-97
        • Schallreuter K.U.
        • Moore J.
        • Wood J.M.
        • Beazley W.D.
        • Gaze D.C.
        • Tobin D.J.
        • et al.
        In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase.
        J Investig Dermatol Symp Proc. 1999; 4: 91-96
        • Schenk B.
        • Fulda S.
        Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death.
        Oncogene. 2015; 34: 5796-5806
        • Shen H.M.
        • Lin Y.
        • Choksi S.
        • Tran J.
        • Jin T.
        • Chang L.
        • et al.
        Essential roles of receptor-interacting protein and TRAF2 in oxidative stress-induced cell death.
        Mol Cell Biol. 2004; 24: 5914-5922
        • Stanger B.Z.
        • Leder P.
        • Lee T.H.
        • Kim E.
        • Seed B.
        RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death.
        Cell. 1995; 81: 513-523
        • Sun L.
        • Wang H.
        • Wang Z.
        • He S.
        • Chen S.
        • Liao D.
        • et al.
        Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase.
        Cell. 2012; 148: 213-227
        • Sun W.
        • Wu X.
        • Gao H.
        • Yu J.
        • Zhao W.
        • Lu J.J.
        • et al.
        Cytosolic calcium mediates RIP1/RIP3 complex-dependent necroptosis through JNK activation and mitochondrial ROS production in human colon cancer cells.
        Free Radic Biol Med. 2017; 108: 433-444
        • Thapa R.J.
        • Nogusa S.
        • Chen P.
        • Maki J.L.
        • Lerro A.
        • Andrake M.
        • et al.
        Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases.
        Proc Natl Acad Sci USA. 2013; 110: E3109-E3118
        • Vanlangenakker N.
        • Bertrand M.J.
        • Bogaert P.
        • Vandenabeele P.
        • Vanden Berghe T.
        TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members.
        Cell Death Dis. 2011; 2: e230
        • Wang H.
        • Sun L.
        • Su L.
        • Rizo J.
        • Liu L.
        • Wang L.F.
        • et al.
        Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3.
        Mol Cell. 2014; 54: 133-146
        • Xie Y.
        • Hou W.
        • Song X.
        • Yu Y.
        • Huang J.
        • Sun X.
        • et al.
        Ferroptosis: process and function.
        Cell Death Differ. 2016; 23: 369-379
        • Yang Z.
        • Wang Y.
        • Zhang Y.
        • He X.
        • Zhong C.Q.
        • Ni H.
        • et al.
        RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis.
        Nat Cell Biol. 2018; 20: 186-197
        • Yatim N.
        • Jusforgues-Saklani H.
        • Orozco S.
        • Schulz O.
        • Barreira da Silva R.
        • Reis e Sousa C.
        • et al.
        RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells.
        Science. 2015; 350: 328-334
        • Yi X.
        • Guo W.
        • Shi Q.
        • Yang Y.
        • Zhang W.
        • Chen X.
        • et al.
        SIRT3-dependent mitochondrial dynamics remodeling contributes to oxidative stress-induced melanocyte degeneration in vitiligo.
        Theranostics. 2019; 9: 1614-1633
        • Zhang M.
        • Li J.
        • Geng R.
        • Ge W.
        • Zhou Y.
        • Zhang C.
        • et al.
        The inhibition of ERK activation mediates the protection of necrostatin-1 on glutamate toxicity in HT-22 cells.
        Neurotox Res. 2013; 24: 64-70
        • Zhang Y.
        • Su S.S.
        • Zhao S.
        • Yang Z.
        • Zhong C.Q.
        • Chen X.
        • et al.
        RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome.
        Nat Commun. 2017; 8: 14329
        • Zhao L.
        • Lin H.
        • Chen S.
        • Chen S.
        • Cui M.
        • Shi D.
        • et al.
        Hydrogen peroxide induces programmed necrosis in rat nucleus pulposus cells through the RIP1/RIP3-PARP-AIF pathway.
        J Orthop Res. 2018; 36: 1269-1282
        • Zhao W.
        • Feng H.
        • Sun W.
        • Liu K.
        • Lu J.J.
        • Chen X.
        Tert-butyl hydroperoxide (t-BHP) induced apoptosis and necroptosis in endothelial cells: roles of NOX4 and mitochondrion.
        Redox Biol. 2017; 11: 524-534
        • Zhou B.
        • Zhang J.Y.
        • Liu X.S.
        • Chen H.Z.
        • Ai Y.L.
        • Cheng K.
        • et al.
        Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis.
        Cell Res. 2018; 28: 1171-1185