title: Autophagy modulates Borrelia burgdorferi-induced production of interleukin-1β (IL-1β).
abstract: Borrelia burgdorferi sensu lato is the causative agent of Lyme disease. Recent studies have shown that recognition of the spirochete is mediated by TLR2 and NOD2. The latter receptor has been associated with the induction of the intracellular degradation process called autophagy. The present study demonstrated for the first time the induction of autophagy by exposure to B. burgdorferi and that autophagy modulates the B. burgdorferi-dependent cytokine production. Human peripheral blood mononuclear cells treated with autophagy inhibitors showed an increased IL-1β and IL-6 production in response to the exposure of the spirochete, whereas TNFα production was unchanged. Autophagy induction against B. burgdorferi was dependent on reactive oxygen species (ROS) because cells from patients with chronic granulomatous disease, which are defective in ROS production, also produced elevated IL-1β. Further, the enhanced production of the proinflammatory cytokines was because of the elevated mRNA expression in the absence of autophagy. Our results thus demonstrate the induction of autophagy, which, in turn, modulates cytokine production by B. burgdorferi for the first time.
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Kathrin
authors: K
authors: Buffen
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Marije
authors: M
authors: Oosting
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors: Svenja
authors: S
authors: Mennens
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors: Paras K
authors: PK
authors: Anand
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Theo S
authors: TS
authors: Plantinga
authors: Department of Microbiology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Patrick
authors: P
authors: Sturm
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Frank L
authors: FL
authors: van de Veerdonk
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Jos W M
authors: JWM
authors: van der Meer
authors: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors: Thirumala-Devi
authors: TD
authors: Kanneganti
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors: Mihai G
authors: MG
authors: Netea
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands; Nijmegen Institute of Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands. Electronic address: l.joosten@aig.umcn.nl.
authors: Leo A B
authors: LAB
authors: Joosten
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D001343:Autophagy; D025065:Borrelia burgdorferi / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C508600:IL6 protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C025946:3-methyladenine; D020170:Caspase 1; D000225:Adenine; D000077191:Wortmannin
references: Blood. 2009 Mar 5;113(10):2324-35
references: 19104081
references: J Immunol. 2001 Aug 1;167(3):1423-30
references: 11466361
references: Front Immunol. 2012 Mar 12;3:44
references: 22566926
references: J Infect Dis. 2010 Jun 15;201(12):1849-58
references: 20441518
references: Ann Agric Environ Med. 2005;12(2):165-72
references: 16457468
references: Cell. 2004 Dec 17;119(6):753-66
references: 15607973
references: Inflamm Bowel Dis. 2009 Nov;15(11):1697-704
references: 19575361
references: Autophagy. 2009 Aug;5(6):887-9
references: 19550142
references: Nat Immunol. 2012 Jan 29;13(3):255-63
references: 22286270
references: Annu Rev Immunol. 2009;27:519-50
references: 19302047
references: Nature. 2008 Nov 13;456(7219):264-8
references: 18849965
references: J Clin Invest. 2008 Feb;118(2):597-607
references: 18202747
references: Infect Immun. 2009 Aug;77(8):3320-7
references: 19487481
references: Blood. 1990 Mar 15;75(6):1305-10
references: 2310829
references: Immunology. 2011 Nov;134(3):341-8
references: 21978003
references: Arthritis Rheum. 2009 Feb;60(2):390-5
references: 19180498
references: PLoS One. 2011;6(10):e25998
references: 21998742
references: J Biol Chem. 2002 Jun 21;277(25):22131-9
references: 11940570
references: J Immunol. 1998 Nov 15;161(10):5762-71
references: 9820558
references: J Immunol. 2009 Oct 15;183(8):5279-92
references: 19794067
references: Annu Rev Pathol. 2008;3:427-55
references: 18039129
references: J Biol Chem. 2012 Feb 3;287(6):4033-40
references: 22167182
references: J Immunol. 2004 Dec 1;173(11):6928-37
references: 15557189
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3683-8
references: 21321205
references: Infect Immun. 2001 Jun;69(6):3618-27
references: 11349022
references: Nat Immunol. 2009 Mar;10(3):241-7
references: 19221555
references: J Immunol. 2009 Dec 15;183(12):7623-9
references: 20007570
references: Autophagy. 2011 Sep;7(9):1074-5
references: 21673517
references: Nat Med. 2011 Feb;17(2):179-88
references: 21217695
references: PLoS One. 2012;7(1):e29695
references: 22295065
references: Hum Genet. 2009 Jun;125(5-6):627-31
references: 19337756
references: Pol Merkur Lekarski. 2004 Nov;17(101):446-50
references: 15754629
references: Infect Immun. 1996 Sep;64(9):3845-52
references: 8751937
references: Nat Med. 2010 Jan;16(1):28-30
references: 20057419
references: Infect Immun. 2008 Jan;76(1):56-70
references: 17938216
references: EMBO J. 2008 Apr 9;27(7):1110-21
references: 18337753
references: Gut. 2011 Sep;60(9):1229-35
references: 21406388
references: EMBO J. 2007 Apr 4;26(7):1749-60
references: 17347651
references: Lancet. 2012 Feb 4;379(9814):461-73
references: 21903253
references: Immunity. 2010 Mar 26;32(3):329-41
references: 20206555
references: Curr Opin Pharmacol. 2012 Aug;12(4):497-502
references: 22342166
references: Infect Immun. 2007 Apr;75(4):2046-62
references: 17220323
references: Science. 2004 Nov 5;306(5698):1037-40
references: 15528445
references: Nat Med. 2010 Jan;16(1):90-7
references: 19966812
references: PLoS One. 2011 Apr 07;6(4):e18666
references: 21490934
references: J Biol Chem. 2011 Dec 16;286(50):42981-91
references: 22033934
references: FEBS Lett. 2010 Jun 18;584(12):2635-45
references: 20412801