scholarly journals Chronic inflammation delays cell migration to villi in the intestinal epithelium

2018 ◽  
Author(s):  
Daniele Muraro ◽  
Aimee Parker ◽  
Laura Vaux ◽  
Sarah Filippi ◽  
Alexander G. Fletcher ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Chronic Inflammation ◽  
Intestinal Epithelium ◽  
Cell Tracking ◽  
Inflammatory Cell ◽  
Epithelial Stem Cells ◽  
Epithelial Homeostasis ◽  
The Impact

AbstractThe intestinal epithelium is a single layer of cells which provides the first line of defence of the intestinal mucosa to bacterial infection. Cohesion of this physical barrier is supported by renewal of epithelial stem cells, residing in invaginations called crypts, and by crypt cell migration onto protrusions called villi; dysregulation of such mechanism may render the gut susceptible to chronic inflammation. The impact that excessive or misplaced epithelial cell death may have on villus cell migration is currently unknown. We integrated cell-tracking methods with computational models to determine how epithelial homeostasis is affected by acute and chronic inflammatory cell death. Parameter inference reveals that acute inflammatory cell death has a transient effect on epithelial cell dynamics, whereas cell death caused by chronic inflammation causes a delay in the accumulation of labelled cells onto the villus compared to control. Such a delay may be reproduced by using a cell-based model to simulate the dynamics of each cell in a crypt-villus geometry, showing that a prolonged increase in cell death slows the migration of cells from the crypt to the villus. This investigation highlights which injuries (acute or chronic) may be regenerated and which cause disruption of healthy epithelial homeostasis.

scholarly journals Chronic TNFα-driven injury delays cell migration to villi in the intestinal epithelium

2018 ◽  
Vol 15 (145) ◽  
pp. 20180037 ◽  
Author(s):  
Daniele Muraro ◽  
Aimee Parker ◽  
Laura Vaux ◽  
Sarah Filippi ◽  
Axel A. Almet ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Cell Tracking ◽  
Computational Models ◽  
Epithelial Stem Cells ◽  
Epithelial Homeostasis ◽  
The Impact ◽  
Epithelial Cell Death

The intestinal epithelium is a single layer of cells which provides the first line of defence of the intestinal mucosa to bacterial infection. Cohesion of this physical barrier is supported by renewal of epithelial stem cells, residing in invaginations called crypts, and by crypt cell migration onto protrusions called villi; dysregulation of such mechanisms may render the gut susceptible to chronic inflammation. The impact that excessive or misplaced epithelial cell death may have on villus cell migration is currently unknown. We integrated cell-tracking methods with computational models to determine how epithelial homeostasis is affected by acute and chronic TNFα-driven epithelial cell death. Parameter inference reveals that acute inflammatory cell death has a transient effect on epithelial cell dynamics, whereas cell death caused by chronic elevated TNFα causes a delay in the accumulation of labelled cells onto the villus compared to the control. Such a delay may be reproduced by using a cell-based model to simulate the dynamics of each cell in a crypt–villus geometry, showing that a prolonged increase in cell death slows the migration of cells from the crypt to the villus. This investigation highlights which injuries (acute or chronic) may be regenerated and which cause disruption of healthy epithelial homeostasis.

scholarly journals Actin dynamics regulation by TTC7A/PI4KIIIα axis limits DNA damage and cell death during leukocyte migration

2021 ◽  
Author(s):  
Tania Gajardo ◽  
Marie Lo ◽  
Mathilde Bernard ◽  
Claire Leveau ◽  
Marie-Therese El-Daher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Leukocyte Migration ◽  
Actin Dynamics ◽  
Immune Homeostasis ◽  
Cellular Functions ◽  
The Impact

The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cell processes, including cell migration. Mutations in the TTC7A gene have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. Although several cellular functions have been associated with TTC7A, the role of the protein in the maintenance of the immune homeostasis is still poorly understood. Here we leverage microfabricated devices to investigate the impact of TTC7A deficiency in leukocytes migration at the single cell level. We show that TTC7A-deficient leukocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositides signaling, leading to the downregulation of the PI3K/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamic. This resulted in impaired cell motility, accumulation of DNA damage and increased cell death during chemotaxis in dense 3D gels. Our results highlight a novel role of TTC7A as a critical regulator of leukocyte migration. Impairment of this cellular function is likely to contribute to pathophysiology underlying progressive immunodeficiency in patients.

scholarly journals Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

2020 ◽  
Author(s):  
Anna Negroni ◽  
Eleonora Colantoni ◽  
Salvatore Cucchiara ◽  
Laura Stronati
Keyword(s):  
Cell Death ◽  
Intestinal Epithelium ◽  
Inflammatory Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Kinase Domain ◽  
Interacting Protein ◽  
New Concepts ◽  
Independent Form ◽  
Cellular Turnover

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

scholarly journals Bacterial infection drives trained immunity through epigenetic remodeling of epithelial stem cells

2021 ◽  
Author(s):  
Scott Hultgren ◽  
Seongmi Russell ◽  
Hyung Joo Lee ◽  
Benjamin Olson ◽  
Jonathan Livny ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Inflammatory Cell ◽  
Host Susceptibility ◽  
Epithelial Stem Cells ◽  
Caspase 1

Abstract Recurrent bacterial infections are a major health burden worldwide, yet the mechanisms dictating host susceptibility to recurrence are poorly understood. Here we demonstrate that an initial bacterial infection of the urinary bladder with uropathogenic E. coli (UPEC) can induce sustained epigenetic changes in the bladder epithelial (urothelial) stem cells that reprogram the differentiated urothelium. We established urothelial stem cell (USC) lines from isogenic mice with different urinary tract infection histories (naïve, chronic or self-resolving). Differentiation of the USC lines in Transwell culture resulted in polarized urothelial cultures that recapitulated distinct remodeling morphologies seen in vivo. In addition, we discovered differences in chromatin accessibility that segregated by disease history, resulting in differences in gene expression upon differentiation of the USC lines in vitro, based on ATAC-seq analysis of the USC lines. Differential basal expression of Caspase-1 led to divergent susceptibilities to inflammatory cell death upon UPEC infection. In mice with a history of chronic infection, enhanced caspase 1-mediated inflammatory cell death was found to be a protective response that enhanced bacterial clearance upon challenge infection. Thus, UPEC infection reshapes the epigenome leading to epithelial-intrinsic remodeling that trains the mucosal immune response to subsequent infection. These findings may have broad implications for the prevention of chronic/recurrent bacterial infections.

scholarly journals Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1431
Author(s):  
Anna Negroni ◽  
Eleonora Colantoni ◽  
Salvatore Cucchiara ◽  
Laura Stronati
Keyword(s):  
Cell Death ◽  
Intestinal Epithelium ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Inflammatory Cell ◽  
Intestinal Inflammation ◽  
Kinase Domain ◽  
Interacting Protein ◽  
New Concepts ◽  
Cellular Turnover

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.

scholarly journals STAT1 coordinates intestinal epithelial cell death during gastrointestinal infection upstream of Caspase-8

2021 ◽  
Author(s):  
Iris Stolzer ◽  
Laura Schickedanz ◽  
Mircea T. Chiriac ◽  
Rocío López-Posadas ◽  
Guntram A. Grassl ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Intestinal Inflammation ◽  
Intestinal Barrier Function ◽  
Caspase 8 ◽  
Intestinal Epithelial ◽  
Gastrointestinal Infection ◽  
Essential Components ◽  
Epithelial Cell Death

AbstractIntestinal homeostasis and the maintenance of the intestinal epithelial barrier are essential components of host defense during gastrointestinal Salmonella Typhimurium infection. Both require a strict regulation of cell death. However, the molecular pathways regulating epithelial cell death have not been completely understood. Here, we elucidated the contribution of central mechanisms of regulated cell death and upstream regulatory components during gastrointestinal infection. Mice lacking Caspase-8 in the intestinal epithelium are highly sensitive towards bacterial induced enteritis and intestinal inflammation, resulting in an enhanced lethality of these mice. This phenotype was associated with an increased STAT1 activation during Salmonella infection. Cell death, barrier breakdown and systemic infection were abrogated by an additional deletion of STAT1 in Casp8ΔIEC mice. In the absence of epithelial STAT1, loss of epithelial cells was abolished which was accompanied by a reduced Caspase-8 activation. Mechanistically, we demonstrate that epithelial STAT1 acts upstream of Caspase-8-dependent as well as -independent cell death and thus might play a major role at the crossroad of several central cell death pathways in the intestinal epithelium. In summary, we uncovered that transcriptional control of STAT1 is an essential host response mechanism that is required for the maintenance of intestinal barrier function and host survival.

scholarly journals A20 and ABIN-1 team up against intestinal epithelial cell death

2018 ◽  
Vol 215 (7) ◽  
pp. 1771-1773
Author(s):  
Ken Cadwell
Keyword(s):  
Cell Death ◽  
Epithelial Cell ◽  
Mouse Model ◽  
Intestinal Epithelium ◽  
Intestinal Epithelial Cell ◽  
Inflammatory Diseases ◽  
Intestinal Epithelial ◽  
Binding Partner ◽  
Epithelial Cell Death

A20 and its binding partner ABIN-1 are genetically linked to inflammatory diseases. In this issue of JEM, Kattah et al. (https://doi.org/10.1084/jem.20180198) demonstrate that simultaneous deletion in a mouse model leads to instantaneous cell death in the intestinal epithelium and mortality.

scholarly journals miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Algera Goga ◽  
Büsra Yagabasan ◽  
Karolin Herrmanns ◽  
Svenja Godbersen ◽  
Pamuditha N. Silva ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Cell Function ◽  
Paneth Cell ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Genetic Ablation ◽  
Epithelial Homeostasis ◽  
Enterocyte Differentiation

AbstractThe intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.

Neutrophil migration through in vitro interstitial matrix

1992 ◽  
Vol 50 (1) ◽  
pp. 894-895
Author(s):  
J. Roemer ◽  
S.R. Simon
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Cell Migration ◽  
Smooth Muscle Cells ◽  
Inflammatory Cell ◽  
Neutrophil Migration ◽  
Culture Conditions ◽  
Aortic Smooth Muscle ◽  
Specific Culture

We are developing an in vitro interstitial extracellular matrix (ECM) system for study of inflammatory cell migration. Falcon brand Cyclopore membrane inserts of various pore sizes are used as a support substrate for production of ECM by R22 rat aortic smooth muscle cells. Under specific culture conditions these cells produce a highly insoluble matrix consisting of typical interstitial ECM components, i.e.: types I and III collagen, elastin, proteoglycans and fibronectin.

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