Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation

dc.contributor.authorMartínez-Sánchez, Luz del Carmen
dc.contributor.authorNgo, Phuong Anh
dc.contributor.authorPradhan, Rashmita
dc.contributor.authorBecker, Lukas-Sebastian
dc.contributor.authorBoehringer, David
dc.contributor.authorSoteriou, Despina
dc.contributor.authorKubankova, Marketa
dc.contributor.authorSchweitzer, Christine
dc.contributor.authorKoch, Tatyana
dc.contributor.authorThonn, Veronika
dc.contributor.authorErkert, Lena
dc.contributor.authorStolzer, Iris
dc.contributor.authorGünther, Claudia
dc.contributor.authorBecker, Christoph
dc.contributor.authorWeigmann, Benno
dc.contributor.authorKlewer, Monika
dc.contributor.authorDaniel, Christoph
dc.contributor.authorAmann, Kerstin
dc.contributor.authorTenzer, Stefan
dc.contributor.authorAtreya, Raja
dc.contributor.authorBergo, Martin
dc.contributor.authorBrakebusch, Cord
dc.contributor.authorWatson, Alastair J M
dc.contributor.authorGuck, Jochen
dc.contributor.authorFabry, Ben
dc.contributor.authorAtreya, Imke
dc.contributor.authorNeurath, Markus F
dc.contributor.authorLópez-Posadas, Rocío
dc.date.accessioned2023-01-17
dc.date.available2023-10-09T20:58:27Z
dc.date.created2023
dc.date.issued2023-01-17
dc.description.abstractObjectiveIncreased apoptotic shedding has been linked to intestinal barrier dysfunction and development of inflammatory bowel diseases (IBD). In contrast, physiological cell shedding allows the renewal of the epithelial monolayer without compromising the barrier function. Here, we investigated the role of live cell extrusion in epithelial barrier alterations in IBD.DesignTaking advantage of conditional GGTase and RAC1 knockout mice in intestinal epithelial cells (Pggt1b iΔIEC and Rac1 iΔIEC mice), intravital microscopy, immunostaining, mechanobiology, organoid techniques and RNA sequencing, we analysed cell shedding alterations within the intestinal epithelium. Moreover, we examined human gut tissue and intestinal organoids from patients with IBD for cell shedding alterations and RAC1 function.ResultsEpithelial Pggt1b deletion led to cytoskeleton rearrangement and tight junction redistribution, causing cell overcrowding due to arresting of cell shedding that finally resulted in epithelial leakage and spontaneous mucosal inflammation in the small and to a lesser extent in the large intestine. Both in vivo and in vitro studies (knockout mice, organoids) identified RAC1 as a GGTase target critically involved in prenylation-dependent cytoskeleton dynamics, cell mechanics and epithelial cell shedding. Moreover, inflamed areas of gut tissue from patients with IBD exhibited funnel-like structures, signs of arrested cell shedding and impaired RAC1 function. RAC1 inhibition in human intestinal organoids caused actin alterations compatible with arresting of cell shedding.ConclusionImpaired epithelial RAC1 function causes cell overcrowding and epithelial leakage thus inducing chronic intestinal inflammation. Epithelial RAC1 emerges as key regulator of cytoskeletal dynamics, cell mechanics and intestinal cell shedding. Modulation of RAC1 might be exploited for restoration of epithelial integrity in the gut of patients with IBD.en
dc.format.extent19
dc.identifier.citationGut 72.2 (2023): S. 275-294. <https://gut.bmj.com/content/72/2/275>
dc.identifier.doihttps://doi.org/10.1136/gutjnl-2021-325520
dc.identifier.issn0017-5749
dc.identifier.issn1468-3288
dc.identifier.opus-id21297
dc.identifier.pmid35241625
dc.identifier.urihttps://open.fau.de/handle/openfau/21297
dc.identifier.urnurn:nbn:de:bvb:29-opus4-212972
dc.language.isoen
dc.publisherBMJ Publishing Group Ltd and British Society of Gastroenterology
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/deed.de
dc.subjectactin cytoskeleton
dc.subjectIBD
dc.subjectepithelial barrier
dc.subjectintestinal epithelium
dc.subjecttight junction
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleEpithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammationen
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.date.prevpublished2023-02-01
local.document.pageend294
local.document.pagestart275
local.journal.issue2
local.journal.titleGut
local.journal.volume72
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.importimport
local.subject.sammlungUniversität Erlangen-Nürnberg / Eingespielte Open Access Artikel / Eingespielte Open Access Artikel 2023
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
21297_gutjnl-72-275.pdf
Size:
13.22 MB
Format:
Adobe Portable Document Format
Description: