scholarly journals Expression of the Alpha8 Integrin Chain Facilitates Phagocytosis by Renal Mesangial Cells

2018 ◽  
Vol 45 (6) ◽  
pp. 2161-2173 ◽  
Author(s):  
Ines Marek ◽  
Robert Becker ◽  
Fabian B. Fahlbusch ◽  
Carlos Menendez-Castro ◽  
Wolfgang Rascher ◽  
...  
Keyword(s):  
Mesangial Cells ◽  
Stress Fibers ◽  
Apoptotic Cells ◽  
Cytoskeletal Reorganization ◽  
Wild Type ◽  
Integrin Receptors ◽  
Facs Analysis ◽  
Latex Beads ◽  
Mesangioproliferative Glomerulonephritis ◽  
Matrix Components

Background/Aims: Healing of mesangioproliferative glomerulonephritis involves degradation of excess extracellular matrix, resolution of hypercellularity by apoptosis and phagocytosis of apoptotic cells. Integrin receptors participate in the regulation of phagocytosis. In mice deficient for alpha8 integrin (Itga8-/-) healing of glomerulonephritis is delayed. As Itga8 is abundant in mesangial cells (MC) which are non-professional phagocytes, we hypothesized that Itga8 facilitates phagocytosis of apoptotic cells and matrix components by MC. Methods: MC were isolated from wild type (WT) and Itga8-/- mice. Latex beads were coated with matrix components. Apoptosis was induced by cisplatin in macrophages and in DiI-stained MC. After coincubation of latex beads or apoptotic cells with MC, the phagocytosis rate was detected in WT and Itga8-/- MC via fluorescence microscopy and FACS analysis. Results: Itga8-/- MC showed reduced phagocytosis of matrix-coated beads and apoptotic cells compared to WT MC. Reduction of stress fibers was observed in Itga8-/- compared to WT MC. Inhibition of cytoskeletal reorganization by inhibition of Rac1 or ROCK during phagocytosis significantly decreased the rate of phagocytosis by WT MC but not by Itga8-/- MC. Conclusion: The expression of Itga8 facilitates phagocytosis in MC, likely mediated by Itga8-cytoskeleton interactions. An impairment of MC phagocytosis might thus contribute to a delayed glomerular regeneration in Itga8-/- mice.

scholarly journals Retinol Saturase Knock-Out Mice are Characterized by Impaired Clearance of Apoptotic Cells and Develop Mild Autoimmunity

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 737 ◽  
Author(s):  
Zsolt Sarang ◽  
Tibor Sághy ◽  
Zsófia Budai ◽  
László Ujlaky-Nagy ◽  
Judit Bedekovics ◽  
...  
Keyword(s):  
Transglutaminase 2 ◽  
Tissue Homeostasis ◽  
Apoptotic Cells ◽  
Wild Type ◽  
Integrin Receptors ◽  
Macrophage Differentiation ◽  
Phagocytic Capacity ◽  
Knock Out ◽  
Knock Out Mice ◽  
Number Of Cells

Apoptosis and the proper clearance of apoptotic cells play a central role in maintaining tissue homeostasis. Previous work in our laboratory has shown that when a high number of cells enters apoptosis in a tissue, the macrophages that engulf them produce retinoids to enhance their own phagocytic capacity by upregulating several phagocytic genes. Our data indicated that these retinoids might be dihydroretinoids, which are products of the retinol saturase (RetSat) pathway. In the present study, the efferocytosis of RetSat-null mice was investigated. We show that among the retinoid-sensitive phagocytic genes, only transglutaminase 2 responded in macrophages and in differentiating monocytes to dihydroretinol. Administration of dihydroretinol did not affect the expression of the tested genes differently between differentiating wild type and RetSat-null monocytes, despite the fact that the expression of RetSat was induced. However, in the absence of RetSat, the expression of numerous differentiation-related genes was altered. Among these, impaired production of MFG-E8, a protein that bridges apoptotic cells to the αvβ3/β5 integrin receptors of macrophages, resulted in impaired efferocytosis, very likely causing the development of mild autoimmunity in aged female mice. Our data indicate that RetSat affects monocyte/macrophage differentiation independently of its capability to produce dihydroretinol at this stage.

Cardiac expression of a gain-of-function α5-integrin results in perinatal lethality

2001 ◽  
Vol 280 (1) ◽  
pp. H361-H367 ◽  
Author(s):  
Maria L. Valencik ◽  
John A. McDonald
Keyword(s):  
Cardiac Development ◽  
Wild Type ◽  
Integrin Receptors ◽  
Gain Of Function ◽  
Transgenic Expression ◽  
Physiological Regulation ◽  
Myocyte Differentiation ◽  
Perinatal Lethality ◽  
And Function

Communication between the extracellular matrix and the intracellular signal transduction and cytoskeletal system is mediated by integrin receptors. α5β1-Integrin and its cognate ligand fibronectin are essential in development of mesodermal structures, myocyte differentiation, and normal cardiac development. To begin to explore the potential roles of α5β1-integrin specifically in cardiomyocytes, we used a transgenic expression strategy. We overexpressed two forms of the human α5-integrin in cardiomyocytes: the full-length wild-type α5-integrin and a putative gain-of-function mutation created by truncating the cytoplasmic domain, designated α5-1-integrin. Overexpression of the wild-type α5-integrin has no detectable adverse effects in the mouse, whereas expression of α5-1-integrin caused electrocardiographic abnormalities, fibrotic changes in the ventricle, and perinatal lethality. Thus physiological regulation of integrin function appears essential for maintenance of normal cardiomyocyte structure and function. This strengthens the role of inside-out signaling in regulation of integrins in vivo and suggests that integrins and associated signaling molecules are important in cardiomyocyte function.

Prosurvival and antiapoptotic effects of PGE2in radiation injury are mediated by EP2 receptor in intestine

2003 ◽  
Vol 284 (3) ◽  
pp. G490-G498 ◽  
Author(s):  
Courtney W. Houchen ◽  
Mark A. Sturmoski ◽  
Shrikant Anant ◽  
Richard M. Breyer ◽  
William F. Stenson
Keyword(s):  
Stem Cell ◽  
Cell Survival ◽  
Cross Section ◽  
Radiation Injury ◽  
Biological Activities ◽  
Receptor Expression ◽  
Apoptotic Cells ◽  
Wild Type ◽  
Γ Irradiation ◽  
Stem Cell Survival

The biological activities of PGE2 are mediated through EP receptors (EP1–EP4), plasma membrane G protein-coupled receptors that differ in ligand binding and signal-transduction pathways. We investigated gastrointestinal EP2 receptor expression in adult mice before and after radiation injury and evaluated intestinal stem cell survival and crypt epithelial apoptosis after radiation injury in EP2 null mice. EP2 was expressed throughout the gut. Intestinal EP2 mRNA increased fivefold after γ-irradiation. Crypt survival was diminished in EP2 −/− mice (4.06 crypts/cross section) compared with wild-type littermates (8.15 crypts/cross section). Radiation-induced apoptosis was significantly increased in EP2 −/− mice compared with wild-type littermates. Apoptosis was 1.6-fold higher in EP2 −/− mice (5.9 apoptotic cells/crypt) than in wild-type mice (3.5 apoptotic cells/crypt). The EP2receptor is expressed in mouse gastrointestinal epithelial cells and is upregulated following radiation injury. The effects of PGE2on both crypt epithelial apoptosis and intestinal crypt stem cell survival are mediated through the EP2 receptor.

The inflammatory macrophage: a story of Jekyll and Hyde

2002 ◽  
Vol 104 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Jeremy S. DUFFIELD
Keyword(s):  
Apoptotic Cells ◽  
Tissue Healing ◽  
Immune Mediated ◽  
Selective Depletion ◽  
The Matrix ◽  
Matrix Components ◽  
The Right ◽  
Extracellular Structures ◽  
Two Populations ◽  
Inflammatory Macrophage

Recent investigations have highlighted new roles for the macrophage (Mϕ) in the biology of inflammation. Selective depletion of Mϕs from inflamed sites has confirmed their predominant role in immune-mediated damage. The components of this injury have been dissected. Mϕs mediate death of stromal, parenchymal and other immune cells by engaging the death programme, resulting in apoptosis. In addition, Mϕs induce destruction of matrix and extracellular structures both directly and indirectly by inducing stromal cells to release matrix metalloproteinases. However, there is another side to the inflammatory Mϕ. Evidence is provided that Mϕs at the same sites possess the ability to aid cell proliferation, secrete and stabilize new matrix components and induce resident cells to secrete matrix components themselves. Mϕ phagocytosis of apoptotic cells brings about a change from the cell-killing matrix-degrading cell to the matrix-generating cell-proliferating tissue-healing cell. Just as both Mϕ types are necessary at the inflamed site, the right balance of these two populations is required for healing and resolution. Evidence of excessive inflammation as a manifestation of impaired phagocytosis of apoptotic cells emphasizes that defects in the transition from one Mϕ type to another may account for the uncontrolled excessive inflammation seen in disease. Recent insights into the mechanisms by which apoptotic cells signal the change of function to the Mϕ offer the prospect of novel targets for manipulation of Mϕs in the inflamed tissue.

scholarly journals Spontaneous Mesangioproliferative Glomerulonephritis in Pigtailed Macaques (Macaca nemestrina)

1981 ◽  
Vol 18 (6_suppl) ◽  
pp. 82-88 ◽  
Author(s):  
J. T. Boyce ◽  
W. E. Giddens ◽  
R. Seifert
Keyword(s):  
Renal Dysfunction ◽  
Cause Of Death ◽  
Immune Complexes ◽  
Mesangial Cells ◽  
Macaca Nemestrina ◽  
Mesangial Matrix ◽  
Ultrastructural Studies ◽  
Mesangioproliferative Glomerulonephritis ◽  
Glomerular Tuft

Mesangioproliferative glomerulonephritis was found in 28 of 113 pigtailed macaques (Macaca nemestrina) that died in 1977. In five it was considered severe enough to cause significant renal dysfunction; in two of these it was the cause of death. The basic lesion was a proliferation of mesangial cells and deposition of mesangial matrix in the mesangial stalk, resulting in various degrees of stalk expansion and increased lobulation of the glomerular tuft. Preliminary immunofluorescence and ultrastructural studies suggest the pathogenesis of the lesion may involve deposition of antigen-IgM immune complexes in the mesangial region.

scholarly journals Vibrio choleraeadapts to sessile and motile lifestyles by cyclic di-GMP regulation of cell shape

2020 ◽  
Vol 117 (46) ◽  
pp. 29046-29054 ◽  
Author(s):  
Nicolas L. Fernandez ◽  
Brian Y. Hsueh ◽  
Nguyen T. Q. Nhu ◽  
Joshua L. Franklin ◽  
Yann S. Dufour ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Shape ◽  
Guanosine Monophosphate ◽  
Human Pathogen ◽  
Flagellar Motility ◽  
Wild Type ◽  
Gene Encoding ◽  
Regulatory Pathways ◽  
Matrix Components ◽  
Curved Rod

The cell morphology of rod-shaped bacteria is determined by the rigid net of peptidoglycan forming the cell wall. Alterations to the rod shape, such as the curved rod, occur through manipulating the process of cell wall synthesis. The human pathogenVibrio choleraetypically exists as a curved rod, but straight rods have been observed under certain conditions. While this appears to be a regulated process, the regulatory pathways controlling cell shape transitions inV. choleraeand the benefits of switching between rod and curved shape have not been determined. We demonstrate that cell shape inV. choleraeis regulated by the bacterial second messenger cyclic dimeric guanosine monophosphate (c-di-GMP) by posttranscriptionally repressing expression ofcrvA, a gene encoding an intermediate filament-like protein necessary for curvature formation inV. cholerae.This regulation is mediated by the transcriptional cascade that also induces production of biofilm matrix components, indicating that cell shape is coregulated withV. cholerae’s induction of sessility. During microcolony formation, wild-typeV. choleraecells tended to exist as straight rods, while genetically engineering cells to maintain high curvature reduced microcolony formation and biofilm density. Conversely, straightV. choleraemutants have reduced swimming speed when using flagellar motility in liquid. Our results demonstrate regulation of cell shape in bacteria is a mechanism to increase fitness in planktonic and biofilm lifestyles.

scholarly journals Long-range cooperative binding of kinesin to a microtubule in the presence of ATP

2005 ◽  
Vol 168 (5) ◽  
pp. 691-696 ◽  
Author(s):  
Etsuko Muto ◽  
Hiroyuki Sakai ◽  
Kuniyoshi Kaseda
Keyword(s):  
Fluorescence Microscopy ◽  
Long Range ◽  
State Transition ◽  
Atp Hydrolysis ◽  
Cooperative Binding ◽  
Adjacent Region ◽  
Wild Type ◽  
Active Involvement ◽  
Latex Beads ◽  
Close Proximity

Interaction of kinesin-coated latex beads with a single microtubule (MT) was directly observed by fluorescence microscopy. In the presence of ATP, binding of a kinesin bead to the MT facilitated the subsequent binding of other kinesin beads to an adjacent region on the MT that extended for micrometers in length. This cooperative binding was not observed in the presence of ADP or 5′-adenylylimidodiphosphate (AMP-PNP), where binding along the MT was random. Cooperative binding also was induced by an engineered, heterodimeric kinesin, WT/E236A, that could hydrolyze ATP, yet remained fixed on the MT in the presence of ATP. Relative to the stationary WT/E236A kinesin on a MT, wild-type kinesin bound preferentially in close proximity, but was biased to the plus-end direction. These results suggest that kinesin binding and ATP hydrolysis may cause a long-range state transition in the MT, increasing its affinity for kinesin toward its plus end. Thus, our study highlights the active involvement of MTs in kinesin motility.

Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif

2009 ◽  
Vol 296 (4) ◽  
pp. F867-F874 ◽  
Author(s):  
Julia Lichtnekert ◽  
Volker Vielhauer ◽  
Daniel Zecher ◽  
Onkar P. Kulkarni ◽  
Sebastian Clauss ◽  
...  
Keyword(s):  
Mesangial Cells ◽  
Apoptotic Cell ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Wild Type ◽  
Tlr Agonists ◽  
Rabbit Igg ◽  
Dying Cells ◽  
Myd88 Signaling ◽  
Deficient Mice

Viral RNA or bacterial products can activate glomerular mesangial cells via a subset of Toll-like receptors (Tlr). Because Tlr2-deficient mice were recently found to have attenuated nephrotoxic serum nephritis (NSN), we hypothesized that endogenous Tlr agonists can activate glomerular mesangial cells. Primary mesangial cells from C57BL/6 mice expressed Tlr1-6 and Tlr11 mRNA at considerable levels and produced Il-6 when being exposed to the respective Tlr ligands. Exposure to necrotic cells activated cultured primary mesangial cells to produce Il-6 in a Tlr2/Myd88-dependent manner. Apoptotic cells activated cultured mesangial cells only when being enriched to high numbers. Apoptotic cell-induced Il-6 release was Myd88 dependent, and only purified apoptotic cell RNA induced Trif signaling in mesangial cells. Does Trif signaling contribute to disease activity in glomerulonephritis? To answer this question, we induced autologous NSN by injection of NS raised in rabbits in Trif-mutant and wild-type mice. Lack of Trif did not alter the functional and histomorphological abnormalities of NSN, including the evolution of anti-rabbit IgG and anti-rabbit-specific nephritogenic T cells. We therefore conclude that apoptotic cell RNA is a poor activator of Trif signaling in mesangial cells and that necrotic cells' releases rather activate mesangial cells via the Tlr2/Myd88 signaling pathway.

scholarly journals Loss of the F-Actin Binding and Vesicle-Associated Protein Comitin Leads to a Phagocytosis Defect

2002 ◽  
Vol 1 (6) ◽  
pp. 906-914 ◽  
Author(s):  
Thomas Schreiner ◽  
Martina R. Mohrs ◽  
Rosemarie Blau-Wasser ◽  
Alfred von Krempelhuber ◽  
Michael Steinert ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Gene Replacement ◽  
Actin Binding ◽  
Wild Type ◽  
Hyperosmotic Shock ◽  
Latex Beads ◽  
Knockout Mutants ◽  
Mutant Cells

ABSTRACT Comitin is an F-actin binding and membrane-associated protein from Dictyostelium discoideum, which is present on Golgi and vesicle membranes and changes its localization in response to agents affecting the cytoskeleton. To investigate its in vivo functions we have generated knockout mutants by gene replacement. Based on comitin's in vitro functions we examined properties related to vesicular transport and microfilament function. Whereas cell growth, pinocytosis, secretion, chemotaxis, motility, and development were unaltered, comitin-lacking cells were impaired in the early steps of phagocytosis of Saccharomyces cerevisiae particles and of Escherichia coli, whereas uptake of latex beads was unaffected. Furthermore, the lack of comitin positively affected survival of pathogenic bacteria. Mutant cells also showed an altered response to hyperosmotic shock in comparison to the wild type. The redistribution of comitin during hyperosmotic shock in wild-type cells and its presence on early phagosomes suggest a direct involvement of comitin in these processes.

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