title: Inflammation and fibrosis during Chlamydia pneumoniae infection is regulated by IL-1 and the NLRP3/ASC inflammasome.
abstract: Chlamydia pneumoniae is a common respiratory pathogen associated with atypical pneumonia, and it has been suggested as a trigger or promoter of several chronic inflammatory conditions, such as asthma and atherosclerosis. The beta form of IL-1 (IL-1beta) is a proinflammatory cytokine released by many cell types and is an important mediator of inflammation during infection. IL-1beta production is a tightly controlled process that includes regulation at multiple levels and typically requires two distinct signals for activation and release. In this study, we investigated the ability of C. pneumoniae to induce IL-1beta secretion. We found that C. pneumoniae was unique among the other Chlamydia species tested in its ability to potently induce secretion of mature IL-1beta from unprimed bone marrow-derived macrophages during a productive infection. TLR2 was required for induction of pro-IL-1beta, whereas the NLRP3/ASC was required for caspase-1 activation and pro-IL-1beta cleavage to produce mature IL-1beta. Caspase-1 cleavage was independent of endogenous ATP release, but required potassium flux, lysosomal acidification, and cathepsin B release. We further investigated the role of IL-1 in host defense against C. pneumoniae-induced pneumonia using mice deficient in the type I IL-1R. Although the IL-1R(-/-) mice developed an inflammatory infiltrate, the number of infiltrating neutrophils was lower, whereas there was evidence of increased infiltrating fibroblasts and mesenchymal cells and more lung fibrosis. We conclude that C. pneumoniae directly activates the NLRP3/ASC inflammasome, leading to the release of biologically active IL-1beta, and that concurrent IL-1 signaling is required for optimal host defense against acute bacterial pneumonia.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Xianbao
authors.initials: X
authors.lastname: He
authors.forename: Samrawit
authors.initials: S
authors.lastname: Mekasha
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Mavrogiorgos
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ingalls
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002690:Chlamydia Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016993:Chlamydophila pneumoniae / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D005355:Fibrosis; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse
references.citation: Nature. 2006 Jul 6;442(7098):39-44
references.pmid: 16823444
references.citation: Nature. 2006 Mar 9;440(7081):237-41
references.pmid: 16407889
references.citation: Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1850-6
references.pmid: 8665045
references.citation: Immunity. 2009 Apr 17;30(4):556-65
references.pmid: 19362020
references.citation: Cell. 2008 Mar 7;132(5):818-31
references.pmid: 18329368
references.citation: J Exp Med. 2009 Jan 16;206(1):79-87
references.pmid: 19139171
references.citation: Nature. 2009 May 21;459(7245):433-6
references.pmid: 19339971
references.citation: J Immunol. 1992 Mar 1;148(5):1486-92
references.pmid: 1531668
references.citation: Am J Clin Nutr. 2006 Feb;83(2):447S-455S
references.pmid: 16470011
references.citation: J Biol Chem. 2006 Nov 17;281(46):35217-23
references.pmid: 16984919
references.citation: Nat Immunol. 2008 Aug;9(8):847-56
references.pmid: 18604214
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000379
references.pmid: 19360122
references.citation: J Biol Chem. 2007 Jun 29;282(26):18810-8
references.pmid: 17491021
references.citation: Am J Respir Crit Care Med. 2001 May;163(6):1384-8
references.pmid: 11371405
references.citation: J Immunol. 2009 Dec 1;183(11):7441-50
references.pmid: 19917678
references.citation: Immunity. 2009 Nov 20;31(5):761-71
references.pmid: 19913447
references.citation: J Immunol. 2006 Apr 1;176(7):3877-83
references.pmid: 16547218
references.citation: PLoS Pathog. 2009 Aug;5(8):e1000559
references.pmid: 19696895
references.citation: Eur J Immunol. 2002 Apr;32(4):1188-95
references.pmid: 11932927
references.citation: Nature. 2006 Mar 9;440(7081):228-32
references.pmid: 16407890
references.citation: Ann Intern Med. 1996 Dec 15;125(12):979-82
references.pmid: 8967709
references.citation: Immunobiology. 2004;209(8):599-608
references.pmid: 15638128
references.citation: Blood. 1996 Mar 15;87(6):2095-147
references.pmid: 8630372
references.citation: Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2308-14
references.pmid: 16179594
references.citation: J Immunol. 2001 Sep 15;167(6):3316-23
references.pmid: 11544320
references.citation: J Biol Chem. 2001 Jan 5;276(1):125-32
references.pmid: 11016935
references.citation: Nat Immunol. 2008 Aug;9(8):857-65
references.pmid: 18604209
references.citation: Eur J Immunol. 2006 May;36(5):1145-55
references.pmid: 16609927
references.citation: Nature. 2004 Jul 8;430(6996):213-8
references.pmid: 15190255
references.citation: Cell Host Microbe. 2009 May 8;5(5):487-97
references.pmid: 19454352
references.citation: Curr Biol. 2004 Nov 9;14(21):1929-34
references.pmid: 15530394
references.citation: Nature. 2008 Jun 19;453(7198):1122-6
references.pmid: 18496530
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1184-90
references.pmid: 11076808
references.citation: Eur J Surg. 2002;168(4):204-14
references.pmid: 12440757
references.citation: Am J Pathol. 1992 Jul;141(1):61-8
references.pmid: 1385928
references.citation: Appl Environ Microbiol. 1996 Feb;62(2):328-31
references.pmid: 8593037
references.citation: N Engl J Med. 1986 Jul 17;315(3):161-8
references.pmid: 3724806
references.citation: Thorax. 2008 Aug;63(8):750-1; author reply 751
references.pmid: 18663076
references.citation: Circ Res. 2001 Aug 3;89(3):244-50
references.pmid: 11485974
references.citation: Immunity. 2009 Apr 17;30(4):566-75
references.pmid: 19362023
references.citation: Thorax. 2008 Mar;63(3):215-20
references.pmid: 17951278
references.citation: Am J Respir Crit Care Med. 1994 Sep;150(3):710-6
references.pmid: 8087341
references.citation: J Immunol. 1999 Mar 1;162(5):2829-36
references.pmid: 10072530
references.citation: J Infect Dis. 2000 Sep;182(3):902-8
references.pmid: 10950787
references.citation: J Biol Chem. 2009 Sep 25;284(39):26789-96
references.pmid: 19648107
references.citation: Circ Res. 2005 Feb 18;96(3):319-26
references.pmid: 15653568
references.citation: Annu Rev Cell Dev Biol. 2002;18:221-45
references.pmid: 12142274
references.citation: J Infect Dis. 2000 Jun;181 Suppl 3:S402-10
references.pmid: 10839724
references.citation: J Immunol. 2009 Jul 15;183(2):787-91
references.pmid: 19570822
references.citation: Curr Allergy Asthma Rep. 2003 Mar;3(2):159-65
references.pmid: 12562556
references.citation: Crit Care Med. 2005 Dec;33(12 Suppl):S460-2
references.pmid: 16340421
references.citation: J Immunol. 1996 Oct 1;157(7):3097-104
references.pmid: 8816420
references.citation: J Biol Chem. 2006 Dec 1;281(48):36560-8
references.pmid: 17008311
references.citation: FEBS Lett. 2007 Feb 20;581(4):587-95
references.pmid: 17257594
references.citation: Nature. 2008 Mar 6;452(7183):103-7
references.pmid: 18288107
references.citation: Immunity. 1999 Oct;11(4):443-51
references.pmid: 10549626
references.citation: J Biol Chem. 2005 Aug 12;280(32):29242-9
references.pmid: 15964841
references.citation: J Immunol. 2002 Feb 1;168(3):1435-40
references.pmid: 11801686
references.citation: Science. 2008 May 2;320(5876):674-7
references.pmid: 18403674
references.citation: J Cell Sci. 2000 Jul;113 ( Pt 13):2455-62
references.pmid: 10852824
references.citation: J Immunol. 1999 Apr 1;162(7):3749-52
references.pmid: 10201887
references.citation: N Engl J Med. 1986 Aug 28;315(9):547-51
references.pmid: 3736638
references.citation: Adv Immunol. 1998;70:83-243
references.pmid: 9755338
references.citation: Eur J Immunol. 1998 Jul;28(7):2066-74
references.pmid: 9692874
references.citation: Infect Immun. 2009 Jul;77(7):2683-90
references.pmid: 19398543