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

O’Shea, Nuala R.; Chew, Thean S; Dunne, Jenny; Marnane, Rebecca; Nedjat-Shokouhi, Bahman; Smith, Philip J.; Bloom, Stuart; Smith, Andrew M.; Segal, Anthony W.

doi:10.1093/ecco-jcc/jjw111

Cited by 30 publications

(33 citation statements)

References 43 publications

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“…As such, macrophage-associated genes downregulated in response to vedolizumab included the costimulatory molecule CD40,50 chemokines ( CXCL9 , CXCL11 , CXCL13 ), phospholipase A1 member A ( PLA1A1 ), which is increased in expression in CD and contributes to the production of proinflammatory lysophospholipids,51 signalling lymphocytic activation molecule (SLAM/ SLAMF1 ), which contributes to myeloid-derived inflammatory cytokine production,52 and proinflammatory chitinase 3-like-1 ( CHI3L1 ,53) (figure 7G). In contrast, we observed increased expression of ADAMDEC1 , a disintegrin and metalloproteinase (ADAM) family member that inhibits intestinal inflammation54 (figure 7G). In conclusion, comprehensive and unbiased analysis of the intestinal transcriptome revealed pronounced vedolizumab-induced alterations in innate immunity that were closely associated with achievement of clinical remission, while treatment-induced changes in adaptive immunity were minor and limited to the Th17 signature.…”

Section: Resultsmentioning

confidence: 86%

Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease

Zeißig

Rosati

Dowds

et al. 2018

Gut

178

180

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ObjectiveVedolizumab, a monoclonal antibody directed against the integrin heterodimer α4β7, is approved for the treatment of Crohn’s disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control.DesignImmunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy.ResultsVedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4β7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation.ConclusionOur findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD.Trial registration numberNCT02694588

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Section: Resultsmentioning

confidence: 86%

Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease

Zeißig

Rosati

Dowds

et al. 2018

Gut

178

180

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“…Its biological function remains unknown, but it has been hypothesised to play a role in immunity. Adamdec1 ‐/‐ mice were more susceptible to the induction of bacterial‐ and chemical‐induced colitis, and greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia …”

Section: Other Investigations To Identify Causal Moleculesmentioning

confidence: 99%

The role of neutrophils in the pathogenesis of Crohn's disease

Segal

2018

Eur J Clin Investigation

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Crohn's disease (CD) is caused by a trigger, almost certainly enteric infection by one of a multitude of organisms that allows faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. In CD the failure of acute inflammation results in the failure to recruit neutrophils to the inflammatory site, as a consequence of which the clearance of bacteria from the tissues is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. Impaired of digestion of bacteria and fungi by CGD neutrophils can result in a similar pathological and clinical picture. The neutrophils in CD are normal and their inadequate accumulation at sites of inflammation generally results from diminished secretion of proinflammatory cytokines by macrophages consequent upon disordered vesicle trafficking.

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“…79 The mRNA encoding ADAMDEC1, which protects the intestines from inflammation, was similarly downregulated. 80 Likewise, the expression of the atypical chemokine receptor ACKR2, which limits branching morphogenesis in the mammary gland, 81 was lower along with another …”

Section: Gsta3mentioning

confidence: 99%

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Gormley

Ona

Kapidzic

et al. 2017

American Journal of Obstetrics and Gynecology

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BACKGROUND:The maternal signs of preeclampsia, which include the new onset of high blood pressure, can occur because of faulty placentation. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would lend new insights into the role of these cells in preeclampsia pathogenesis. OBJECTIVE: Our goal was to enrich syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts from the placentas of severe preeclampsia cases. Total RNA was subjected to global transcriptional profiling to identify RNAs that were misexpressed compared with controls. STUDY DESIGN: This was a cross-sectional analysis of placentas from women who had been diagnosed with severe preeclampsia. Gestational age-matched controls were placentas from women who had a preterm birth with no signs of infection. Laser microdissection enabled enrichment of syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts. After RNA isolation, a microarray approach was used for global transcriptional profiling. Immunolocalization identified changes in messenger RNA expression that carried over to the protein level. Differential expression of noneprotein-coding RNAs was confirmed by in situ hybridization. A 2-way analysis of variance of non-coding RNA expression identified particular classes that distinguished trophoblasts in cases vs controls. Cajal body foci were visualized by coilin immunolocalization. RESULTS: Comparison of the trophoblast subtype data within each group (severe preeclampsia or noninfected preterm birth) identified many highly differentially expressed genes. They included molecules that are known to be expressed by each subpopulation, which is evidence that the method worked. Genes that were expressed differentially between the 2 groups, in a cell-typeespecific manner, encoded a combination of molecules that previous studies associated with severe preeclampsia and those that were not known to be dysregulated in this pregnancy

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

Cited by 30 publications

References 43 publications

Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease

Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease

The role of neutrophils in the pathogenesis of Crohn's disease

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

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