Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis
| Autor: | Chew, Thean S., O'Shea, Nuala R., Sewell, Gavin W., Oehlers, Stefan H., Mulvey, Claire M., Crosier, Philip S., Godovac-Zimmermann, Jasminka, Bloom, Stuart L., Smith, Andrew M., Segal, Anthony W. |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Inheritance Patterns Golgi Apparatus lcsh:Medicine Cell Cycle Proteins Models Biological Polymorphism Single Nucleotide Mice Citrobacter Crohn Disease Transcription Factor TFIIIA TNFα Escherichia coli lcsh:Pathology Animals Humans Eye Proteins Escherichia coli Infections Zebrafish Bacteria Tumor Necrosis Factor-alpha Macrophages lcsh:R Membrane Transport Proteins Middle Aged Colitis Up-Regulation Crohn's disease Neutrophil Infiltration Case-Control Studies Cytokines Female Inflammation Mediators Research Article lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms, Vol 8, Iss 8, Pp 817-829 (2015) Disease Models & Mechanisms |
| ISSN: | 1754-8403 1754-8411 |
| Popis: | 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. Summary: Optineurin plays a role in acute inflammation, proinflammatory cytokine secretion and neutrophil recruitment, which suggests that diminished optineurin expression in humans might increase the risk of developing Crohn's disease. |
| Databáze: | OpenAIRE |
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