De Novo sphingolipid synthesis is essential for Salmonella-induced autophagy and human beta-defensin 2 expression in intestinal epithelial cells
Tóm tắt
Sphingolipids are important for innate immune response to eliminate infected pathogens and involved in autophagy. On the other hand, nucleotide-binding oligomerization domain-containing protein 2 (NOD2) served as an intracellular pattern recognition receptor to enhance host defense by inducing autophagy and the production of antimicrobial peptides, such as human beta-defensin-2 (hBD-2). However, the role of sphingolipids in Salmonella-induced autophagy and hBD-2 response in intestinal epithelial cells has not been previously elucidated.
Salmonella typhimurium wild-type strain SL1344 was used to infect SW480, an intestinal epithelial cell. hBD-2 and interleukin-8 (IL-8) mRNA expressions were assessed in SW480 cells using RT-PCR, and intracellular signaling pathways and autophagy protein expression were analyzed by Western blot in SW480 cells in the presence or absence of inhibitors or transfected with siRNA. We demonstrated that inhibition of de novo sphingolipid synthesis repressed the membrane recruitment of NOD2 and autophagy-related protein 16-like 1 (Atg16L1), suppressed Salmonella-induced autophagic protein LC3-II expression, and reduced NOD2-mediated hBD-2 response in Salmonella-infected SW480 cells. Contrasting to the utilization of membrane cholesterol on maintenance of Salmonella-containing vacuoles and anti-inflammation by Salmonella, sphingolipids act on epithelial defense against the invasive pathogen. Our results offer mechanistic insights on the role of de novo sphingolipid synthesis in the innate immunity of intestinal epithelial cells to Salmonella infection. The pharmaceuticals enhancing or diet enriched with sphingolipids may induce the dual anti-bacterial mechanisms. The role of de novo sphingolipid synthesis on inflammatory bowel disease is deserved to be further investigated.
Tài liệu tham khảo
Gulbins E, Dreschers S, Wilker B, Grassme H. Ceramide, membrane rafts and infections. J Mol Med (Berl). 2004;82(6):357–63. doi:10.1007/s00109-004-0539-y.
Grassme H, Jendrossek V, Riehle A, von Kurthy G, Berger J, Schwarz H, et al. Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med. 2003;9(3):322–30. doi:10.1038/nm823.17.
Hanada K. Sphingolipids in infectious diseases. Jpn J Infect Dis. 2005;58(3):131–48.
Jiang W, Ogretmen B. Autophagy paradox and ceramide. Biochim Biophys Acta. 2014;1841(5):783–92. doi:10.1016/j.bbalip.2013.09.005.
Park JW, Park WJ, Futerman AH. Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim Biophys Acta. 2014;1841(5):671–81. doi:10.1016/j.bbalip.2013.08.019.
Yamagata M, Obara K, Kihara A. Sphingolipid synthesis is involved in autophagy in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2011;410(4):786–91. doi:10.1016/j.bbrc.2011.06.061.
Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11(1):55–62. doi:10.1038/ni.1823.
Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16(1):90–7. doi:10.1038/nm.2069.
Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J. NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem. 2006;281(4):2005–11. doi:10.1074/jbc.M511044200.
Huang GT, Zhang HB, Kim D, Liu L, Ganz T. A model for antimicrobial gene therapy: demonstration of human beta-defensin 2 antimicrobial activities in vivo. Hum Gene Ther. 2002;13(17):2017–25. doi:10.1089/10430340260395875.
Lasserre R, Guo XJ, Conchonaud F, Hamon Y, Hawchar O, Bernard AM, et al. Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation. Nat Chem Biol. 2008;4(9):538–47. doi:10.1038/nchembio.103.
Knodler LA, Finlay BB, Steele-Mortimer O. The Salmonella effector protein SopB protects epithelial cells from apoptosis by sustained activation of Akt. J Biol Chem. 2005;280(10):9058–64. doi:10.1074/jbc.M412588200.18.
Birmingham CL, Brumell JH. Autophagy recognizes intracellular Salmonella enterica serovar Typhimurium in damaged vacuoles. Autophagy. 2006;2(3):156–8.
Huang FC. The critical role of membrane cholesterol in salmonella-induced autophagy in intestinal epithelial cells. Int J Mol Sci. 2014;15(7):12558–72. doi:10.3390/ijms150712558.
Young MM, Kester M, Wang HG. Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res. 2013;54(1):5–19. doi:10.1194/jlr.R031278.
Poole K, Meder D, Simons K, Muller D. The effect of raft lipid depletion on microvilli formation in MDCK cells, visualized by atomic force microscopy. FEBS Lett. 2004;565(1–3):53–8. doi:10.1016/j.febslet.2004.03.095.
Schwan C, Nolke T, Kruppke AS, Schubert DM, Lang AE, Aktories K. Cholesterol- and sphingolipid-rich microdomains are essential for microtubule-based membrane protrusions induced by Clostridium difficile transferase (CDT). J Biol Chem. 2011;286(33):29356–65. doi:10.1074/jbc.M111.261925.
Hidari K, Ichikawa S, Fujita T, Sakiyama H, Hirabayashi Y. Complete removal of sphingolipids from the plasma membrane disrupts cell to substratum adhesion of mouse melanoma cells. J Biol Chem. 1996;271(24):14636–41.
Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition. J Cell Biol. 2005;170(1):21–6. doi:10.1083/jcb.200502153.
Gulbins E, Bissonnette R, Mahboubi A, Martin S, Nishioka W, Brunner T, et al. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity. 1995;2(4):341–51.
Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature. 1996;380(6569):75–9. doi:10.1038/380075a0.
Huang FC, Li Q, Cherayil BJ. A phosphatidyl-inositol-3-kinase-dependent anti-inflammatory pathway activated by Salmonella in epithelial cells. FEMS Microbiol Lett. 2005;243(1):265–70. doi:10.1016/j.femsle.2004.12.013.19.
Sanjuan MA, Milasta S, Green DR. Toll-like receptor signaling in the lysosomal pathways. Immunol Rev. 2009;227(1):203–20. doi:10.1111/j.1600-065X.2008.00732.x.
Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology. 2010;139(5):1630–41. doi:10.1053/j.gastro.2010.07.006 (e1–2).
Conway KL, Kuballa P, Song JH, Patel KK, Castoreno AB, Yilmaz OH, et al. Atg16l1 is Required for Autophagy in Intestinal Epithelial Cells and Protection of Mice from Salmonella Infection. Gastroenterology. 2013;. doi:10.1053/j.gastro.2013.08.035.
Oswald IP, Desautels C, Laffitte J, Fournout S, Peres SY, Odin M, et al. Mycotoxin fumonisin B1 increases intestinal colonization by pathogenic Escherichia coli in pigs. Appl Environ Microbiol. 2003;69(10):5870–4.
Lapaquette P, Darfeuille-Michaud A. Abnormalities in the handling of intracellular bacteria in Crohn’s disease. J Clin Gastroenterol. 2010;44(Suppl 1):S26–9. doi:10.1097/MCG.0b013e3181dd4fa5.
Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ. Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant. PLoS One. 2008;3(10):e3391. doi:10.1371/journal.pone.0003391.
Kurek K, Lukaszuk B, Piotrowska DM, Wiesiolek P, Chabowska AM, Zendzian-Piotrowska M. Metabolism, physiological role, and clinical implications of sphingolipids in gastrointestinal tract. BioMed Res Int. 2013;2013:908907. doi:10.1155/2013/908907.
Jess T, Simonsen J, Nielsen NM, Jorgensen KT, Bager P, Ethelberg S, et al. Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease. Gut. 2011;60(3):318–24. doi:10.1136/gut.2010.223396.
Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011;140(6):1729–37. doi:10.1053/j.gastro.2011.02.012.
Aldhous MC, Noble CL, Satsangi J. Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One. 2009;4(7):e6285. doi:10.1371/journal.pone.0006285.20.
Zilbauer M, Jenke A, Wenzel G, Postberg J, Heusch A, Phillips AD, et al. Expression of human beta-defensins in children with chronic inflammatory bowel disease. PLoS One. 2010;5(10):e15389. doi:10.1371/journal.pone.0015389.
Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4 + CD25 + regulatory T cells. J Immunol. 2007;178(4):2458–68.
Brown DA, London E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem. 2000;275(23):17221–4. doi:10.1074/jbc.R000005200.
Helms JB, Zurzolo C. Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic. 2004;5(4):247–54. doi:10.1111/j.1600-0854.2004.0181.x.
Huang FC. Plasma membrane cholesterol plays a critical role in the Salmonella-induced anti-inflammatory response in intestinal epithelial cells. Cell Immunol. 2011;271(2):480–7. doi:10.1016/j.cellimm.2011.08.018.
Mao-Qiang M, Feingold KR, Elias PM. Inhibition of cholesterol and sphingolipid synthesis causes paradoxical effects on permeability barrier homeostasis. J Invest Dermatol. 1993;101(2):185–90.
Huang FC. Regulation of Salmonella flagellin-induced interleukin-8 in intestinal epithelial cells by muramyl dipeptide. Cell Immunol. 2012;278(1–2):1–9. doi:10.1016/j.cellimm.2012.06.013.
Huang FC. Differential regulation of interleukin-8 and human beta-defensin 2 in Pseudomonas aeruginosa -infected intestinal epithelial cells. BMC Microbiol. 2014;14(1):275. doi:10.1186/s12866-014-0275-6.