Chew, TS;
O'Shea, NR;
Sewell, GW;
Oehlers, SH;
Mulvey, CM;
Crosier, PS;
Godovac-Zimmermann, J;
... Segal, AW; + view all
(2015)
Optineurin deficiency contributes to impaired cytokine secretion and neutrophil recruitment in bacteria driven colitis.
Disease Models & Mechanisms
, 8
(8)
817- 829.
10.1242/dmm.020362.
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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, we performed transcriptomic analysis in macrophages and identified a subgroup of CD patients with low expression of the autophagy receptor optineurin (OPTN). Here we clarified the role of OPTN deficiency in macrophage cytokine secretion, models of bacteria driven colitis and peritonitis in mice and zebrafish Salmonella infection. OPTN deficient bone-marrow derived macrophages (BMDM) stimulated with heat-killed E. coli secreted less proinflammatory TNF and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors suggesting that TNF is mistrafficked 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 with reduced levels of proinflammatory TNF in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality. 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 may increase the risk of developing CD.
| Type: | Article |
|---|---|
| Title: | Optineurin deficiency contributes to impaired cytokine secretion and neutrophil recruitment in bacteria driven colitis. |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/dmm.020362 |
| Publisher version: | http://dx.doi.org/10.1242/dmm.020362 |
| Language: | English |
| Additional information: | © 2015. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1470153 |
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