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

Chew, Thean S; O’Shea, Nuala R.; Sewell, Gavin W.; Oehlers, Stefan H.; Mulvey, Claire M.; Crosier, Philip S.; Godovac‐Zimmermann, Jasminka; Bloom, Stuart; Smith, Andrew M.; Segal, Anthony W.

doi:10.1242/dmm.020362

Cited by 49 publications

(48 citation statements)

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“…C. rodentium was prepared and administered as previously described. 42 Adamdec1 -/ - and Adamdec1 +/+ mice at 9–12 weeks old were orally gavaged 10 8 or 10 9 colony-forming units [CFU] of C. rodentium .…”

Section: Methodsmentioning

confidence: 99%

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

O’Shea

Chew

Dunne

et al. 2016

ECCOJC

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Background and Aims:ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn’s disease patients has provided evidence of a potential role in bowel inflammation.Methods:Adamdec1-/- mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium. The clinical response was monitored.Results:The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia.Conclusion:In summary, ADAMDEC1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn’s disease.

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Section: Methodsmentioning

confidence: 99%

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

O’Shea

Chew

Dunne

et al. 2016

ECCOJC

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“…Macrophages from patients with low expression of OPTN secreted abnormally low levels of pro-inflammatory cytokines as do macrophages from OPTN knock out mice 357 . mRNA expression levels of these cytokines were normal, consistent with deranged secretion rather than synthesis.…”

Section: Other Investigations To Identify Causal Moleculesmentioning

confidence: 94%

Making sense of the cause of Crohn’s – a new look at an old disease

Segal

2016

F1000Res

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The cause of Crohn’s disease (CD) has posed a conundrum for at least a century. A large body of work coupled with recent technological advances in genome research have at last started to provide some of the answers. Initially this review seeks to explain and to differentiate between bowel inflammation in the primary immunodeficiencies that generally lead to very early onset diffuse bowel inflammation in humans and in animal models, and the real syndrome of CD. In the latter, a trigger, almost certainly enteric infection by one of a multitude of organisms, allows the faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. Direct investigation of patients’ inflammatory response together with genome-wide association studies (GWAS) and DNA sequencing indicate that in CD the failure of acute inflammation and the clearance of bacteria from the tissues, and from within cells, is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. In this review I will examine the contemporary evidence that has led to this understanding, and look for explanations for the recent dramatic increase in the incidence of this disease.

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“…Page 19 of 34 F1000Research 2016, 5:2510 Last updated: 25 DEC 2016 Macrophages from patients with low expression of OPTN secreted abnormally low levels of pro-inflammatory cytokines as do macrophages from OPTN knock out mice 354 . mRNA expression levels of these cytokines were normal, consistent with deranged secretion rather than synthesis.…”

Section: Other Investigations To Identify Causal Molecules Macrophagementioning

confidence: 99%

“…OPTN-knockdown zebrafish infected with Salmonella also had a higher mortality 354 . ADAMDEC1 (ADAM-like Decysin-1) is a member of the ADAM (A Disintegrin And Metalloproteinase) family, the expression of which is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract.…”

mentioning

confidence: 97%

“…Myosin VI is attached by OPTN to the Golgi apparatus and then it participates in the transport of vesicles and their protein cargos from the from the Trans-Golgi network to be released at the cell surface. OPTN also contains a ubiquitin binding domain with the ability to bind polyubiquitinated cargoes and transport them to autophagosomes via its microtubule-associated protein 1 light chain 3-interacting domain 353 .Page 19 of 34 F1000Research 2016, 5:2510 Last updated: 25 DEC 2016 Macrophages from patients with low expression of OPTN secreted abnormally low levels of pro-inflammatory cytokines as do macrophages from OPTN knock out mice 354 . mRNA expression levels of these cytokines were normal, consistent with deranged secretion rather than synthesis.…”

mentioning

confidence: 99%

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Making sense of the cause of Crohn’s – a new look at an old disease

Segal¹

2016

F1000Res

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The cause of Crohn's disease (CD) has posed a conundrum for at least a century. A large body of work coupled with recent technological advances in genome research have at last started to provide some of the answers. Initially this review seeks to explain and to differentiate between bowel inflammation in the primary immunodeficiencies that generally lead to very early onset diffuse bowel inflammation in humans and in animal models, and the real syndrome of CD. In the latter, a trigger, almost certainly enteric infection by one of a multitude of organisms, allows the faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. Direct investigation of patients' inflammatory response together with genome-wide association studies (GWAS) and DNA sequencing indicate that in CD the failure of acute inflammation and the clearance of bacteria from the tissues, and from within cells, is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. In this review I will examine the contemporary evidence that has led to this understanding, and look for explanations for the recent dramatic increase in the incidence of this disease. General introductionThe enigma that is the cause of Crohn's disease (CD) has puzzled clinicians and scientists from time immemorial. It is generally accepted that CD results from an aberrant immune response to commensal microflora in genetically susceptible individuals 1 , however, the nature of the immune defects, the responsible microflora and the genetic susceptibility remain incompletely defined and actively debated. With advances in genomic technologies our understanding of this puzzling condition is evolving, and answers forthcoming. The purpose of this article is to undertake a holistic review of the aetiopathogenesis of CD in which historical concepts are integrated with recent discoveries.The bowel mucosa, an interface between faeces and the tissues The distal ileum and colon contain >10 11 bacteria per gram of faecal material 2 , which pose an immediate threat to life if they penetrate into the underlying tissues. The bowel microflora are isolated by a thin film of mucus and a single layer of columnar epithelial cells with a surface area of approximately 32m 2 , 3 . The requirement for the absorption of fluids and nutrients by the bowel mucosa means that the bowel lining cannot simply be a tough impermeable barrier, and as a consequence provision must be made to defend the vulnerable mucosal epithelial cell layer against its contents. Mucus secreted by goblet cells forms a continuous, weak, viscoelastic gel, lining, 5-500 μm thick 4 . In addition to acting as a physical barrier and lubricant, the mucus is the site of action of a variety of antimicrobial mechanisms including secretory IgA, antimicrobial enzymes and peptides 5 and H 2 O 2 generated by the DUOX electron transport chain 6 . Despite these barriers, the separation of the tissues from the gut microbiome...

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

Cited by 49 publications

References 64 publications

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

Making sense of the cause of Crohn’s – a new look at an old disease

Making sense of the cause of Crohn’s – a new look at an old disease

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