Optineurin deficiency contributes to impaired cytokine secretion and neutrophil recruitment in bacteria driven colitis
- Chew, T.S., O'Shea, N.R., Sewell, G.W., Oehlers, S.H., Mulvey, C.M., Crosier, P.S., Godovac-Zimmermann, J., Bloom, S.L., Smith, A.M., Segal, A.W.
- Disease models & mechanisms 8(8): 817-29 (Journal)
- Registered Authors
- Crosier, Phil, Oehlers, Stefan
- Crohn's disease, Macrophages, TNFα Escherichia coli, Cytokines
- MeSH Terms
- Case-Control Studies
- Crohn Disease/genetics
- Crohn Disease/microbiology
- Escherichia coli/physiology
- Escherichia coli Infections/prevention & control
- Eye Proteins/metabolism*
- Golgi Apparatus/metabolism
- Inflammation Mediators/metabolism
- Inheritance Patterns/genetics
- Middle Aged
- Models, Biological
- Neutrophil Infiltration*
- Polymorphism, Single Nucleotide/genetics
- Transcription Factor TFIIIA/deficiency
- Transcription Factor TFIIIA/metabolism
- Tumor Necrosis Factor-alpha/metabolism
- 26044960 Full text @ Dis. Model. Mech.
Chew, T.S., O'Shea, N.R., Sewell, G.W., Oehlers, S.H., Mulvey, C.M., Crosier, P.S., Godovac-Zimmermann, J., Bloom, S.L., Smith, A.M., Segal, A.W. (2015) Optineurin deficiency contributes to impaired cytokine secretion and neutrophil recruitment in bacteria driven colitis. Disease models & mechanisms. 8(8):817-29.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes