title: Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.
abstract: Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD.
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK.
authors.forename: Thean S
authors.initials: TS
authors.lastname: Chew
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK.
authors.forename: Nuala R
authors.initials: NR
authors.lastname: O'Shea
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK.
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Sewell
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1001, New Zealand.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Oehlers
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Mulvey
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1001, New Zealand.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Crosier
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Godovac-Zimmermann
authors.affiliation: Department of Gastroenterology, University College London Hospital, London, NW1 2BU, UK.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Bloom
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK Microbial Diseases, Eastman Dental Institute, University College London, London, WC1X 8LD, UK andrew.m.smith@ucl.ac.uk.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Division of Medicine, University College London, London, WC1E 6JF, UK.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
mesh_terms: D000328:Adult; D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D002954:Citrobacter / Q000502:physiology; D003092:Colitis / Q000097:blood / Q000382:microbiology / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000382:microbiology; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004926:Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000517:prevention & control; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D040582:Inheritance Patterns / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D020556:Neutrophil Infiltration; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D035582:Transcription Factor TFIIIA / Q000172:deficiency / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D015027:Zebrafish
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D005136:Eye Proteins; D018836:Inflammation Mediators; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; C501288:Optn protein, mouse; D035582:Transcription Factor TFIIIA; D014409:Tumor Necrosis Factor-alpha
keywords: Crohn's disease; Cytokines; Escherichia coli; Macrophages; TNFα