PMID- 26044960
OWN - NLM
STAT- MEDLINE
DCOM- 20160419
LR  - 20220129
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Print)
IS  - 1754-8403 (Linking)
VI  - 8
IP  - 8
DP  - 2015 Aug 1
TI  - Optineurin deficiency in mice contributes to impaired cytokine secretion and 
      neutrophil recruitment in bacteria-driven colitis.
PG  - 817-29
LID - 10.1242/dmm.020362 [doi]
AB  - 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 TNFalpha and IL6 cytokines 
      despite similar gene transcription, which normalised with lysosomal and autophagy 
      inhibitors, suggesting that TNFalpha 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 TNFalpha 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.
CI  - (c) 2015. Published by The Company of Biologists Ltd.
FAU - Chew, Thean S
AU  - Chew TS
AD  - Division of Medicine, University College London, London, WC1E 6JF, UK.
FAU - O'Shea, Nuala R
AU  - O'Shea NR
AD  - Division of Medicine, University College London, London, WC1E 6JF, UK.
FAU - Sewell, Gavin W
AU  - Sewell GW
AD  - Division of Medicine, University College London, London, WC1E 6JF, UK.
FAU - Oehlers, Stefan H
AU  - Oehlers SH
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland 
      1001, New Zealand.
FAU - Mulvey, Claire M
AU  - Mulvey CM
AD  - Division of Medicine, University College London, London, WC1E 6JF, UK Department 
      of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK.
FAU - Crosier, Philip S
AU  - Crosier PS
AD  - Department of Molecular Medicine and Pathology, University of Auckland, Auckland 
      1001, New Zealand.
FAU - Godovac-Zimmermann, Jasminka
AU  - Godovac-Zimmermann J
AD  - Division of Medicine, University College London, London, WC1E 6JF, UK.
FAU - Bloom, Stuart L
AU  - Bloom SL
AD  - Department of Gastroenterology, University College London Hospital, London, NW1 
      2BU, UK.
FAU - Smith, Andrew M
AU  - Smith AM
AD  - 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.
FAU - Segal, Anthony W
AU  - Segal AW
AD  - Division of Medicine, University College London, London, WC1E 6JF, UK.
LA  - eng
GR  - G0902005/MRC_/Medical Research Council/United Kingdom
GR  - MR/L000261/1/MRC_/Medical Research Council/United Kingdom
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150604
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Cytokines)
RN  - 0 (Eye Proteins)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (OPTN protein, human)
RN  - 0 (Optn protein, mouse)
RN  - 0 (Transcription Factor TFIIIA)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Bacteria/*metabolism
MH  - Case-Control Studies
MH  - Cell Cycle Proteins
MH  - Citrobacter/physiology
MH  - Colitis/blood/microbiology/pathology
MH  - Crohn Disease/genetics/microbiology
MH  - Cytokines/blood/*metabolism
MH  - Escherichia coli/physiology
MH  - Escherichia coli Infections/prevention & control
MH  - Eye Proteins/*metabolism
MH  - Female
MH  - Golgi Apparatus/metabolism
MH  - Humans
MH  - Inflammation Mediators/metabolism
MH  - Inheritance Patterns/genetics
MH  - Macrophages/metabolism
MH  - Male
MH  - Membrane Transport Proteins
MH  - Mice
MH  - Middle Aged
MH  - Models, Biological
MH  - *Neutrophil Infiltration
MH  - Polymorphism, Single Nucleotide/genetics
MH  - Transcription Factor TFIIIA/deficiency/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Up-Regulation
MH  - Zebrafish
PMC - PMC4527293
OTO - NOTNLM
OT  - Crohn's disease
OT  - Cytokines
OT  - Escherichia coli
OT  - Macrophages
OT  - TNFalpha
COIS- Competing interests The authors declare no competing or financial interests.
EDAT- 2015/06/06 06:00
MHDA- 2016/04/20 06:00
PMCR- 2015/08/01
CRDT- 2015/06/06 06:00
PHST- 2015/02/18 00:00 [received]
PHST- 2015/05/11 00:00 [accepted]
PHST- 2015/06/06 06:00 [entrez]
PHST- 2015/06/06 06:00 [pubmed]
PHST- 2016/04/20 06:00 [medline]
PHST- 2015/08/01 00:00 [pmc-release]
AID - dmm.020362 [pii]
AID - DMM020362 [pii]
AID - 10.1242/dmm.020362 [doi]
PST - ppublish
SO  - Dis Model Mech. 2015 Aug 1;8(8):817-29. doi: 10.1242/dmm.020362. Epub 2015 Jun 4.