8,817
Views
8
CrossRef citations to date
0
Altmetric
Research Paper

Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD

, , ORCID Icon, , ORCID Icon, , , , , ORCID Icon, , , , , , ORCID Icon, , , ORCID Icon, , , , , , & show all
Pages 92-111 | Received 03 Nov 2021, Accepted 01 Apr 2022, Published online: 26 Apr 2022

References

  • Ghosh S, Stepicheva N, Yazdankhah M, et al. The role of lipocalin-2 in age-related macular degeneration (AMD). Cell Mol Life Sci. 2020 Mar;77(5):835–851. PMID: 31901947.
  • Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011 Feb;11(2):85–97. PMID: 21252989.
  • Jaberi SA, Cohen A, D’Souza C, et al. Lipocalin-2: structure, function, distribution and role in metabolic disorders. Biomed Pharmacother. 2021 Oct;142:112002. PMID: 34463264.
  • Golonka R, Yeoh BS, Vijay-Kumar M. The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity. PMID: 30605903. J Innate Immun. 2019 Jan;11(3):249–262.
  • Halaas O, Steigedal M, Haug M, et al. Intracellular Mycobacterium avium intersect transferrin in the Rab11(+) recycling endocytic pathway and avoid lipocalin 2 trafficking to the lysosomal pathway. J Infect Dis. 2010 Mar;201(5):783–792. PMID: 20121435.
  • Hvidberg V, Jacobsen C, Strong RK, et al. The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett. 2005 Jan;579(3):773–777. PMID: 15670845.
  • Ghosh S, Padmanabhan A, Vaidya T, et al. Neutrophils homing into the retina trigger pathology in early age-related macular degeneration. Commun Biol. 2019 Sep;2(1):348. PMID: 31552301.
  • Valapala M, Edwards M, Hose S, et al. Increased Lipocalin-2 in the retinal pigment epithelium of Cryba1 cKO mice is associated with a chronic inflammatory response. Aging Cell. 2014 Dec;13(6):1091–1094. PMID: 25257511.
  • Viau A, El Karoui K, Laouari D, et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest. 2010 Nov;120(11):4065–4076. PMID: 20921623.
  • Santiago-Sánchez GS, Pita-Grisanti V, Quiñones-Díaz B, et al. Biological functions and therapeutic potential of lipocalin 2 in cancer. Int J Mol Sci. 2020 Jun;21(12):4365. PMID: 32575507.
  • Barasch J, Hollmen M, Deng R, et al. Disposal of iron by a mutant form of lipocalin 2. Nat Commun. 2016 Oct;7(1):12973. PMID: 27796299.
  • Axelsson L, Bergenfeldt M, Ohlsson K. Studies of the release and turnover of a human neutrophil lipocalin. PMID: 8633182. Scand J Clin Lab Invest. 1995 Nov;55(7):577–588.
  • Singh V, Yeoh BS, Chassaing B, et al. Microbiota-inducible Innate Immune, siderophore binding protein lipocalin 2 is critical for intestinal homeostasis. Cell Mol Gastroenterol Hepatol. 2016 Jul;2(4):482–498.e6. PMID: 27458605.
  • Rehwald C, Schnetz M, Urbschat A, et al. The iron load of lipocalin-2 (LCN2) defines its pro-tumour function in clear-cell renal cell carcinoma. Br J Cancer. 2020 Feb;122(3):421–433. PMID: 31772326.
  • Ghosh S, Shang P, Yazdankhah M, et al. Activating the AKT2-nuclear factor-?B-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration. J Pathol. 2017 Apr;241(5):583–588. PMID: 28026019.
  • Parmar T, Parmar VM, Arai E, et al. Acute stress responses are early molecular events of retinal degeneration in Abca4-/-Rdh8-/- mice after light exposure. Invest Ophthalmol Vis Sci. 2016 Jun;57(7):3257–3267. PMID: 27315541.
  • Chen M, Yang N, Lechner J, et al. Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis. Immun Ageing. 2020 Nov;17(1):35. PMID: 33292361.
  • Schroll A, Eller K, Feistritzer C, et al. Lipocalin-2 ameliorates granulocyte functionality. Eur J Immunol. 2012 Dec;42(12):3346–3357. PMID: 22965758.
  • Chakraborty S, Kaur S, Guha S, et al. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta. 2012 Aug;1826(1):129–169. PMID: 22513004.
  • Maruyama T, Noda NN. Autophagy-regulating protease Atg4: structure, function, regulation and inhibition. PMID: 28901328. J Antibiot (Tokyo). 2017 Sep;71(1):72–78.
  • Wang C, Zhang R, Wei X, et al. Metalloimmunology: the metal ion-controlled immunity. Adv Immunol. 2020 PMID: 32081198;145:187–241.
  • Shang P, Valapala M, Grebe R, et al. The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling. Aging Cell. 2017 Apr;16(2):349–359. PMID: 28083894.
  • Valapala M, Wilson C, Hose S, et al. Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/ßA3/A1-crystallin via V-ATPase-MTORC1 signaling. Autophagy. 2014 Mar;10(3):480–496. PMID: 24468901.
  • Chan YK, Sung HK, Jahng JW, et al. Lipocalin-2 inhibits autophagy and induces insulin resistance in H9c2 cells. Mol Cell Endocrinol. 2016 Jul;430:68–76. PMID: 27090568.
  • Sung HK, Chan YK, Han M, et al. Lipocalin-2 (NGAL) attenuates autophagy to exacerbate cardiac apoptosis induced by myocardial ischemia. J Cell Physiol. 2017 Aug;232(8):2125–2134. PMID: 27800610.
  • Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. PMID: 29618831. Nat Rev Mol Cell Biol. 2018 Jun;19(6):349–364.
  • Huynh K, Partch CL. Analysis of protein stability and ligand interactions by thermal shift assay. PMID: 25640896. Curr Protoc Protein Sci. 2015 Feb;79(1):28.9.1–28.9.14.
  • Layton CJ, Hellinga HW. Quantitation of protein-protein interactions by thermal stability shift analysis. PMID: 21674662. Protein Sci. 2011 Aug;20(8):1439–1450.
  • Kaizuka T, Morishita H, Hama Y, et al. An Autophagic Flux Probe that releases an internal control. Mol Cell. 2016 Nov 17;64(4):835–849. PMID: 27818143.
  • Intartaglia D, Giamundo G, Conte I. Autophagy in the retinal pigment epithelium: a new vision and future challenges. FEBS J. 2021 May; Epub ahead of print. PMID: 33993621. 10.1111/febs.16018
  • Tan W, Zou J, Yoshida S, et al. The role of inflammation in age-related macular degeneration. Int J Biol Sci. 2020 Sep;16(15):2989–3001. PMID: 33061811.
  • Yu C, Roubeix C, Sennlaub F, et al. Microglia versus monocytes: distinct roles in degenerative diseases of the retina. Trends Neurosci. 2020 Jun;43(6):433–449. PMID: 3245999.
  • Mauthe M, Orhon I, Rocchi C, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435–1455. PMID: 29940786.
  • Jacomin AC, Geraki K, Brooks J, et al. Impact of autophagy and aging on iron load and ferritin in drosophila brain. Front Cell Dev Biol. 2019 Jul;7:142. PMID: 31404236.
  • Masaldan S, Clatworthy SAS, Gamell C, et al. Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol. 2018 Apr;14:100–115. PMID: 28888202.
  • Hedbrant A, Andersson L, Bryngelsson IL, et al. Quartz dust exposure affects NLRP3 inflammasome activation and plasma levels of IL-18 and IL-1Ra in iron foundry workers. Mediators Inflamm. 2020 Jan;2020:8490908. PMID: 32256196.
  • Li C, Zhang Y, Cheng X, et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev Cell. 2018 Aug;46(4):441–455.e8. PMID: 30100261.
  • Gelfand BD, Wright CB, Kim Y, et al. Iron toxicity in the retina requires alu RNA and the NLRP3 inflammasome. Cell Rep. 2015 Jun;11(11):1686–1693. PMID: 26074074.
  • Handa JT, Bowes Rickman C, Dick AD, et al. A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration. Nat Commun. 2019 Jul;10(1):3347. PMID: 31350409.
  • Biasizzo M, Kopitar-Jerala N. Interplay between NLRP3 inflammasome and autophagy. Front Immunol. 2020 Oct;11:591803. PMID: 33163006.
  • Zhao S, Li X, Wang J, et al. The role of the effects of autophagy on NLRP3 inflammasome in inflammatory nervous system diseases. Front Cell Dev Biol. 2021 May;9:657478. PMID: 34079796.
  • Iacovelli J, Zhao C, Wolkow N, et al. Generation of Cre transgenic mice with postnatal RPE-specific ocular expression. Invest Ophthalmol Vis Sci. 2011 Mar;52(3):1378–1383. PMID: 21212186.
  • Vodicka P, Lim J, Williams DT, et al. Assessment of chloroquine treatment for modulating autophagy flux in brain of WT and HD mice. J Huntingtons Dis. 2014;3(2):159–174. PMID: 25062859.
  • Hong L, Simon JD. Current understanding of the binding sites, capacity, affinity, and biological significance of metals in melanin. PMID: 17580858. J Phys Chem B. 2007 Jul;111(28):7938–7947.
  • Wiriyasermkul P, Moriyama S, Nagamori S. Membrane transport proteins in melanosomes: regulation of ions for pigmentation. PMID: 32333855. Biochim Biophys Acta Biomembr. 2020 Dec;1862(12):183318.
  • Wolkow N, Song Y, Wu TD, et al. Aceruloplasminemia: retinal histopathologic manifestations and iron-mediated melanosome degradation. Arch Ophthalmol. 2011 Nov;129(11):1466–1474. PMID: 22084216.
  • Wolkow N, Li Y, Maminishkis A, et al. Iron upregulates melanogenesis in cultured retinal pigment epithelial cells. Exp Eye Res. 2014 Nov;128:92–101. PMID: 25277027.
  • Zhu W, Zhao Z, Cheng B. The role of autophagy in skin pigmentation. PMID: 33262098. Eur J Dermatol. 2020 Dec;30(6):655–662.
  • Juuti-Uusitalo K, Koskela A, Kivinen N, et al. Autophagy regulates proteasome inhibitor-induced pigmentation in human embryonic stem cell-derived retinal pigment epithelial cells. Int J Mol Sci. 2017;18(5):1089. PMID: 28534814.
  • Berson JF, Harper DC, Tenza D, et al. Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol Biol Cell. 2001 Nov;12(11):3451–3464. PMID: 11694580.
  • Lopes VS, Wasmeier C, Seabra MC, et al. Melanosome maturation defect in Rab38-deficient retinal pigment epithelium results in instability of immature melanosomes during transient melanogenesis. Mol Biol Cell. 2007 Oct;18(10):3914–3927. PMID: 17671165.
  • Martín-Sánchez F, Diamond C, Zeitler M, et al. Inflammasome-dependent IL-1ß release depends upon membrane permeabilisation. Cell Death Differ. 2016 Jul;23(7):1219–1231. PMID: 26868913.
  • Decout A, Katz JD, Venkatraman S, et al. The CGAS-STING1 pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021 Sep;21(9):548–569. PMID: 33833439.
  • Kerur N, Fukuda S, Banerjee D. CGAS drives noncanonical-inflammasome activation in age-related macular degeneration. PMID: 29176737. Nat Med. 2018 Jan;24(1):50–61.
  • Cappellini MD, Musallam KM, Taher AT. Overview of iron chelation therapy with desferrioxamine and deferiprone. Hemoglobin. 2009;33(Suppl sup1):S58–69. PMID: 20001633.
  • Hong Z, Mei J, Li C, et al. STING inhibitors target the cyclic dinucleotide binding pocket. Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118. PMID: 34099558.
  • He L, He T, Farrar S, et al. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem. 2017;44(2):532–553. PMID: 29145191.
  • Mazhar M, Din AU, Ali H, et al. Implication of ferroptosis in aging. Cell Death Discov. 2021 Jun;7(1):149. PMID: 34226536.
  • Li C, Liu J, Hou W, et al. STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion. Front Cell Dev Biol. 2021 Jun;9:698679. PMID: 34195205.
  • Omar RA, Chyan YJ, Andorn AC, et al. Increased expression but reduced activity of antioxidant enzymes in alzheimer’s disease. J Alzheimers Dis. 1999 Oct;1(3):139–145. PMID: 12213999.
  • Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020 Feb;11(2):88. PMID: 32015325.
  • Luchi K, Nishimaki K, Kamimura N, et al. Molecular hydrogen suppresses free-radical-induced cell death by mitigating fatty acid peroxidation and mitochondrial dysfunction. Can J Physiol Pharmacol. 2019 Oct;97(10):999–1005. PMID: 31295412.
  • Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014 Jan;156(1–2):317–331. PMID: 24439385.
  • Miotto G, Rossetto M, Di Paolo ML, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 2020 Jan;28:101328. PMID: 31574461.
  • Jin D, Zhang Y, Chen X. Lipocalin 2 deficiency inhibits cell proliferation, autophagy, and mitochondrial biogenesis in mouse embryonic cells. PMID: 21234651. Mol Cell Biochem. 2011 May;351(1–2):165–172.
  • Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2):e106–16. PMID: 25104651.
  • Whitcup SM, Sodhi A, Atkinson JP, et al. The role of the immune response in age-related macular degeneration. Int J Inflam. 2013 PMID: 23762772;2013:348092.
  • Wang J, Zibetti C, Shang P, et al. ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration. Nat Commun. 2018 Apr;9(1):1364. PMID: 29636475.
  • Mariño G, Fernández AF, Cabrera S, et al. Autophagy is essential for mouse sense of balance. J Clin Invest. 2010 Jul;120(7):2331–2344. PMID: 20577052.
  • Ratnapriya R, Sosina OA, Starostik MR, et al. Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration. Nat Genet. 2019 Apr;51(4):606–610. PMID: 30742112.
  • Hadziahmetovic M, Song Y, Wolkow N, et al. Bmp6 regulates retinal iron homeostasis and has altered expression in age-related macular degeneration. Am J Pathol. 2011 Jul;179(1):335–348. PMID: 21703414.
  • Shi CS, Shenderov K, Huang NN, et al. Activation of autophagy by inflammatory signals limits IL-1ß production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012 Jan;13(3):255–263. PMID: 22286270.
  • Gonugunta VK, Sakai T, Pokatayev V, et al. Trafficking-Mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep. 2017 Dec;21(11):3234–3242. PMID: 29241549.
  • Chu TT, Tu X, Yang K, et al. Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C. Nature. 2021 Aug;596(7873):570–575. PMID: 34290407.
  • Lv H, Zhu C, Wei W, et al. Enhanced Keap1-Nrf2/Trx-1 axis by daphnetin protects against oxidative stress-driven hepatotoxicity via inhibiting ASK1/JNK and Txnip/NLRP3 inflammasome activation. Phytomedicine. 2020 Jun;71:153241. PMID: 32454347.
  • Cheng YC, Chu LW, Chen JY, et al. Loganin attenuates high glucose-induced schwann cells pyroptosis by inhibiting ROS generation and NLRP3 inflammasome activation. Cells. 2020 Aug;9(9):1948. PMID: 32842536.
  • Ligeon LA, Pena-Francesch M, Vanoaica LD, et al. Oxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation. Nat Commun. 2021 Mar;12(1):1508. PMID: 33686057.
  • Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020 Nov;66:89–100. PMID: 30880243.
  • Han C, Liu Y, Dai R, et al. Ferroptosis and its potential role in human diseases. Front Pharmacol. 2020 Mar;11:239. PMID: 32256352.
  • Chen M, Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration. PMID: 26292978. J Leukoc Biol. 2015 Nov;98(5):713–725.
  • Shang P, Stepicheva N, Teel K, et al. ßA3/A1-crystallin regulates apical polarity and EGFR endocytosis in retinal pigmented epithelial cells. Commun Biol. 2021 Jul;4(1):850. PMID: 34239035.
  • Chothe PP, Gnana-Prakasam JP, Ananth S, et al. Transport of hepcidin, an iron-regulatory peptide hormone, into retinal pigment epithelial cells via oligopeptide transporters and its relevance to iron homeostasis. Biochem Biophys Res Commun. 2011 Feb;405(2):244–249. PMID: 21219868.
  • Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan;541(7638):481–487. PMID: 28099414.
  • Sweigard JH, Cashman SM, Kumar-Singh R. Adenovirus vectors targeting distinct cell types in the retina. PMID: 19892875. Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2219–2228.
  • Ghosh S, Liu H, Yazdankhah M, et al. ßA1-crystallin regulates glucose metabolism and mitochondrial function in mouse retinal astrocytes by modulating PTP1B activity. Commun Biol. 2021 Feb;4(1):248. PMID: 33627831.
  • Bolte S, Cordelières FP. A guided tour into subcellular colocalization analysis in light microscopy. PMID: 17210054. J Microsc. 2006 Dec;224(Pt 3):213–232.
  • Hao Y, Hao S, Andersen-Nissen E, et al. Integrated analysis of multimodal single-cell data. Cell. 2021 Jun;184(13):3573–3587.e29. PMID: 34062119.
  • Yazdankhah M, Ghosh S, Shang P, et al. BNIP3L-mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes. Autophagy. 2021 Oct;17(10):3140–3159. PMID: 33404293.
  • Pengo N, Agrotis A, Prak K, et al. A reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B. Nat Commun. 2017 Aug;8(1):294. PMID: 28821708.
  • Ghosh S, Choudhury S, Chowdhury O, et al. Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: role of fluoxetine. Cell Signal. 2020 Apr;68:109521. PMID: 31881324.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.