دورية أكاديمية
أعرض في EDS

Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.

التفاصيل البيبلوغرافية
العنوان: Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.
المؤلفون: Chew TS; Division of Medicine, University College London, London, WC1E 6JF, UK., O'Shea NR; Division of Medicine, University College London, London, WC1E 6JF, UK., Sewell GW; Division of Medicine, University College London, London, WC1E 6JF, UK., Oehlers SH; Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1001, New Zealand., Mulvey CM; Division of Medicine, University College London, London, WC1E 6JF, UK Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK., Crosier PS; Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1001, New Zealand., Godovac-Zimmermann J; Division of Medicine, University College London, London, WC1E 6JF, UK., Bloom SL; Department of Gastroenterology, University College London Hospital, London, NW1 2BU, UK., Smith AM; 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., Segal AW; Division of Medicine, University College London, London, WC1E 6JF, UK.
المصدر: Disease models & mechanisms [Dis Model Mech] 2015 Aug 01; Vol. 8 (8), pp. 817-29. Date of Electronic Publication: 2015 Jun 04.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge : Company of Biologists Ltd., c2008-
مواضيع طبية MeSH: Neutrophil Infiltration*, Bacteria/*metabolism , Cytokines/*metabolism , Eye Proteins/*metabolism, Adult ; Animals ; Case-Control Studies ; Cell Cycle Proteins ; Citrobacter/physiology ; Colitis/blood ; Colitis/microbiology ; Colitis/pathology ; Crohn Disease/genetics ; Crohn Disease/microbiology ; Cytokines/blood ; Escherichia coli/physiology ; Escherichia coli Infections/prevention & control ; Female ; Golgi Apparatus/metabolism ; Humans ; Inflammation Mediators/metabolism ; Inheritance Patterns/genetics ; Macrophages/metabolism ; Male ; Membrane Transport Proteins ; Mice ; Middle Aged ; Models, Biological ; Polymorphism, Single Nucleotide/genetics ; Transcription Factor TFIIIA/deficiency ; Transcription Factor TFIIIA/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation ; Zebrafish
مستخلص: 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.
(© 2015. Published by The Company of Biologists Ltd.)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; G0902005 United Kingdom MRC_ Medical Research Council; MR/L000261/1 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: Crohn's disease; Cytokines; Escherichia coli; Macrophages; TNFα
المشرفين على المادة: 0 (Cell Cycle Proteins)
0 (Cytokines)
0 (Eye Proteins)
0 (Inflammation Mediators)
0 (Membrane Transport Proteins)
0 (OPTN protein, human)
0 (Optn protein, mouse)
0 (Transcription Factor TFIIIA)
0 (Tumor Necrosis Factor-alpha)
تواريخ الأحداث: Date Created: 20150606 Date Completed: 20160419 Latest Revision: 20240708
رمز التحديث: 20240708
مُعرف محوري في PubMed: PMC4527293
DOI: 10.1242/dmm.020362
PMID: 26044960
قاعدة البيانات: MEDLINE
الوصف
تدمد:1754-8411
DOI:10.1242/dmm.020362