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Lactosylceramide-accumulation in lipid-rafts mediate aberrant-autophagy, inflammation and apoptosis in cigarette smoke induced emphysema

  • THE ROLE OF SPHINGOLIPIDS AND LIPID RAFTS IN DETERMINING CELL FATE
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Abstract

Ceramide-accumulation is known to be involved in the pathogenesis of chronic inflammatory lung diseases including cigarette smoke-induced emphysema (CS-emphysema) but the exact sphingolipid metabolite that initiates emphysema progression remains ambiguous. We evaluated here a novel role for the sphingolipid, lactosylceramide (LacCer), as a potential mechanism for pathogenesis of CS-emphysema. We assessed the expression of LacCer, and LacCer-dependent inflammatory, apoptosis and autophagy responses in lungs of mice exposed to CS, as well as peripheral lung tissues from COPD subjects followed by experimental analysis to verify the role of LacCer in CS-emphysema. We observed significantly elevated LacCer-accumulation in human COPD lungs with increasing severity of emphysema over non-emphysema controls. Moreover, increased expression of defective-autophagy marker, p62, in lung tissues of severe COPD subjects suggest that LacCer induced aberrant-autophagy may contribute to the pathogenesis of CS-emphysema. We verified that CS-extract treatment significantly induces LacCer-accumulation in both bronchial-epithelial cells (BEAS2B) and macrophages (Raw264.7) as a mechanism to initiate aberrant-autophagy (p62-accumulation) and apoptosis that was rescued by pharmacological inhibitor of LacCer-synthase. Further, we corroborated that CS exposure induces LacCer-accumulation in murine lungs that can be controlled by LacCer-synthase inhibitor. We propose LacCer-accumulation as a novel prognosticator of COPD-emphysema severity, and provide evidence on the therapeutic efficacy of LacCer-synthase inhibitor in CS induced COPD-emphysema.

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References

  1. Barnes PJ (2003) New concepts in chronic obstructive pulmonary disease. Annu Rev Med 54:113–129

    Article  CAS  PubMed  Google Scholar 

  2. MacNee W (2005) Oxidants and COPD. Curr Drug Targets Inflamm Allergy 4(6):627–641

    Article  CAS  PubMed  Google Scholar 

  3. van Houwelingen AH, Weathington NM, Verweij V, Blalock JE, Nijkamp FP, Folkerts G (2008) Induction of lung emphysema is prevented by l-arginine-threonine-arginine. FASEB J 22(9):3403–3408

    Article  PubMed Central  PubMed  Google Scholar 

  4. Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, Gaggar A, Shastry S, Rowe SM, Shim YM, Hussell T, Blalock JE (2010) A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330(6000):90–94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Barnes PJ, Shapiro SD, Pauwels RA (2003) Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 22(4):672–688

    Article  CAS  PubMed  Google Scholar 

  6. Bodas M, Min T, Mazur S, Vij N (2011) Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema. J Immunol 186(1):602–613

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Teichgraber V, Ulrich M, Endlich N, Riethmuller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kurthy G, Schmid KW, Weller M, Tummler B, Lang F, Grassme H, Doring G, Gulbins E (2008) Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 14(4):382–391

    Article  PubMed  Google Scholar 

  8. Bodas M, Min T, Vij N (2011) Critical role of CFTR dependent lipid-rafts in cigarette smoke induced lung epithelial injury. Am J Physiol Lung Cell Mol Physiol 300(6):L811–L820

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Elias JA, Lee CG (2005) Lipid let loose in pulmonary emphysema. Nat Med 11(5):471–472

    Article  CAS  PubMed  Google Scholar 

  10. Uhlig S, Gulbins E (2008) Sphingolipids in the lungs. Am J Respir Crit Care Med 178(11):1100–1114

    Article  CAS  PubMed  Google Scholar 

  11. Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM (2005) Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med 11(5):491–498

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Brodlie M, McKean MC, Johnson GE, Gray J, Fisher AJ, Corris PA, Lordan JL, Ward C (2010) Ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 182(3):369–375

    Article  CAS  PubMed  Google Scholar 

  13. Guilbault C, De Sanctis JB, Wojewodka G, Saeed Z, Lachance C, Skinner TA, Vilela RM, Kubow S, Lands LC, Hajduch M, Matouk E, Radzioch D (2008) Fenretinide corrects newly found ceramide deficiency in cystic fibrosis. Am J Respir Cell Mol Biol 38(1):47–56

    Article  CAS  PubMed  Google Scholar 

  14. Mu H, Wang X, Wang H, Lin P, Yao Q, Chen C (2009) Lactosylceramide promotes cell migration and proliferation through activation of ERK1/2 in human aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 297(1):H400–H408

    Article  CAS  PubMed  Google Scholar 

  15. Arai T, Bhunia AK, Chatterjee S, Bulkley GB (1998) Lactosylceramide stimulates human neutrophils to upregulate Mac-1, adhere to endothelium, and generate reactive oxygen metabolites in vitro. Circ Res 82(5):540–547

    Article  CAS  PubMed  Google Scholar 

  16. Pannu R, Singh AK, Singh I (2005) A novel role of lactosylceramide in the regulation of tumor necrosis factor alpha-mediated proliferation of rat primary astrocytes. Implications for astrogliosis following neurotrauma. J Biol Chem 280(14):13742–13751

    Article  CAS  PubMed  Google Scholar 

  17. Chatterjee S, Pandey A (2008) The Yin and Yang of lactosylceramide metabolism: implications in cell function. Biochim Biophys Acta 1780(3):370–382

    Article  CAS  PubMed  Google Scholar 

  18. Chatterjee S, Shi WY, Wilson P, Mazumdar A (1996) Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease. J Lipid Res 37(6):1334–1344

    CAS  PubMed  Google Scholar 

  19. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, Belenky A, Bukanov NO, Dackowski WR, Husson H, Russo RJ, Shayman JA, Ledbetter SR, Leonard JP, Ibraghimov-Beskrovnaya O (2010) Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med 16(7):788–792

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Tran I, Ji C, Ni I, Min T, Tang D, Vij N (2014) Role of cigarette smoke-induced aggresome-formation in COPD-emphysema pathogenesis. Am J Respir Cell Mol Biol. doi:10.1165/rcmb.2014-0107OC

    Google Scholar 

  21. Min T, Bodas M, Mazur S, Vij N (2011) Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med (Berl) 89(6):577–593

    Article  CAS  Google Scholar 

  22. Nyunoya T, Monick MM, Klingelhutz A, Yarovinsky TO, Cagley JR, Hunninghake GW (2006) Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol 35(6):681–688

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Pannu R, Won JS, Khan M, Singh AK, Singh I (2004) A novel role of lactosylceramide in the regulation of lipopolysaccharide/interferon-gamma-mediated inducible nitric oxide synthase gene expression: implications for neuroinflammatory diseases. J Neurosci 24(26):5942–5954

    Article  CAS  PubMed  Google Scholar 

  24. Luciani A, Villella VR, Esposito S, Brunetti-Pierri N, Medina D, Settembre C, Gavina M, Pulze L, Giardino I, Pettoello-Mantovani M, D’Apolito M, Guido S, Masliah E, Spencer B, Quaratino S, Raia V, Ballabio A, Maiuri L (2010) Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol 12(9):863–875

    Article  CAS  PubMed  Google Scholar 

  25. Martin SF, Williams N, Chatterjee S (2006) Lactosylceramide is required in apoptosis induced by N-Smase. Glycoconj J 23(3–4):147–157

    Article  CAS  PubMed  Google Scholar 

  26. Zhang Y, Li X, Becker KA, Gulbins E (2009) Ceramide-enriched membrane domains—structure and function. Biochim Biophys Acta 1788(1):178–183

    Article  CAS  PubMed  Google Scholar 

  27. Muppidi JR, Tschopp J, Siegel RM (2004) Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity 21(4):461–465

    Article  CAS  PubMed  Google Scholar 

  28. Grassme H, Cremesti A, Kolesnick R, Gulbins E (2003) Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22(35):5457–5470

    Article  CAS  PubMed  Google Scholar 

  29. Volonte D, Galbiati F (2009) Caveolin-1, cellular senescence and pulmonary emphysema. Aging (Albany NY) 1(9):831–835

    CAS  Google Scholar 

  30. McDonald G, Deepak S, Miguel L, Hall CJ, Isenberg DA, Magee AI, Butters T, Jury EC (2014) Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. The J Clin Invest 124(2):712–724. doi:10.1172/JCI69571

  31. Vij N, Amoaka MO, Mazur S, Zeitlin P (2008) CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol 38(2):176–184

  32. Aouali N, El Btaouri H, Dumontet C, Eddabra L, Malagarie-Cazenave S, Madoulet C, Morjani H (2011) Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells. Oncol Rep 25(4):1161–1167

    CAS  PubMed  Google Scholar 

  33. Bismuth J, Chai H, Lin PH, Yao Q, Chen C (2009) Lactosylceramide causes endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells. Med Sci Monit 15(9):270–274

    Google Scholar 

  34. Won JS, Singh AK, Singh I (2007) Lactosylceramide: a lipid second messenger in neuroinflammatory disease. J Neurochem 103(Suppl 1):180–191

    Article  CAS  PubMed  Google Scholar 

  35. Karman J, Tedstone JL, Gumlaw NK, Zhu Y, Yew N, Siegel C, Guo S, Siwkowski A, Ruzek M, Jiang C, Cheng SH (2010) Reducing glycosphingolipid biosynthesis in airway cells partially ameliorates disease manifestations in a mouse model of asthma. Int Immunol 22(7):593–603

    Article  CAS  PubMed  Google Scholar 

  36. Chen ZH, Lam HC, Jin Y, Kim HP, Cao J, Lee SJ, Ifedigbo E, Parameswaran H, Ryter SW, Choi AM (2010) Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci USA 107(44):18880–18885

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Cantin AM, Hanrahan JW, Bilodeau G, Ellis L, Dupuis A, Liao J, Zielenski J, Durie P (2006) Cystic fibrosis transmembrane conductance regulator function is suppressed in cigarette smokers. Am J Respir Crit Care Med 173(10):1139–1144

    Article  CAS  PubMed  Google Scholar 

  38. Vij N, Downey GP (2013) The yin and yang of cystic fibrosis transmembrane conductance regulator function: implications for chronic lung disease. Am J Respir Crit Care Med 187(2):120–122

  39. Keller CA (2003) Pathophysiology and classification of emphysema. Chest Surg Clin N Am 13(4):589–613

    Article  PubMed  Google Scholar 

  40. Fromer L, Cooper CB (2008) A review of the GOLD guidelines for the diagnosis and treatment of patients with COPD. Int J Clin Pract 62(8):1219–1236. doi:10.1111/j.1742-1241.2008.01807.x

    Article  CAS  PubMed  Google Scholar 

  41. Riccardi C, Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1(3):1458–1461

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

NV was supported by Flight Attendants Medical Research Institute (FAMRI) and National Institute of Health (CTSA UL RR 025005, RHL096931 and U54CA141868) Grants. We would like to thank Lung Tissue Research Consortium LTRC (NHLBI, NIH) for human lung tissue samples.

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Author notes

  1. Manish Bodas

    Present address: CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, 110007, India

  2. Taehong Min

    Present address: Genentech, 1DNA Way, San Francisco, CA, USA

Authors and Affiliations

  1. Department of Pediatric Respiratory Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Manish Bodas & Neeraj Vij

  2. Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Taehong Min

  3. College of Medicine, Central Michigan University, 2630 Denison Drive, Room# 120 (Office) & 126-127 (Lab), College of Medicine Research Building, Mt. Pleasant, MI, 48859, USA

    Neeraj Vij

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  1. Manish Bodas
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Correspondence to Neeraj Vij.

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Bodas, M., Min, T. & Vij, N. Lactosylceramide-accumulation in lipid-rafts mediate aberrant-autophagy, inflammation and apoptosis in cigarette smoke induced emphysema. Apoptosis 20, 725–739 (2015). https://doi.org/10.1007/s10495-015-1098-0

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