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4 results on '"Cera MR"'

1. JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling.

Author

Cera MR, Fabbri M, Molendini C, Corada M, Orsenigo F, Rehberg M, Reichel CA, Krombach F, Pardi R, and Dejana E

Subjects
Animals, Cell Adhesion Molecules genetics, Cell Line, Tumor, Chelating Agents pharmacology, Chemotaxis drug effects, Cytoplasmic Vesicles physiology, Egtazic Acid analogs & derivatives, Egtazic Acid pharmacology, Humans, Immunoglobulins genetics, Integrin beta1 drug effects, Leukotriene B4 pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, N-Formylmethionine Leucyl-Phenylalanine analogs & derivatives, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophils drug effects, Oligopeptides pharmacology, Receptors, Cell Surface genetics, Cell Adhesion Molecules metabolism, Chemotaxis physiology, Immunoglobulins metabolism, Integrin beta1 metabolism, Neutrophils physiology, Receptors, Cell Surface metabolism, rap1 GTP-Binding Proteins metabolism
Abstract

The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin beta1. Clustering of beta1 integrin leads to JAM-A co-clustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize beta1 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.

Published
2009
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2. Expression of junctional adhesion molecule-A prevents spontaneous and random motility.

Author

Bazzoni G, Tonetti P, Manzi L, Cera MR, Balconi G, and Dejana E

Subjects
Animals, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cell Communication physiology, Cell Line, Transformed, Cell Movement drug effects, Cell Surface Extensions metabolism, Endothelial Cells metabolism, Enzyme Inhibitors pharmacology, Focal Adhesions metabolism, Gene Expression, Glycogen Synthase Kinase 3 antagonists & inhibitors, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Indoles pharmacology, Lithium pharmacology, Maleimides pharmacology, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Knockout, Microtubules metabolism, Phosphorylation drug effects, Protein Kinase C antagonists & inhibitors, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Cell Adhesion Molecules physiology, Cell Movement physiology, Endothelial Cells cytology, Receptors, Cell Surface physiology
Abstract

Junctional adhesion molecule-A (JAM-A) is a cell-surface glycoprotein that localizes to intercellular junctions and associates with intracellular proteins via PSD95-Dlg-ZO1-binding residues. To define the functional consequences of JAM-A expression, we have produced endothelial cells from JAM-A-deficient mice. We report here that the absence of JAM-A enhanced spontaneous and random motility. In turn, the enhanced motility of JAM-A-negative cells was abrogated either on transfection of exogenous JAM-A or on treatment with inhibitors of glycogen synthase kinase-3beta (GSK-3beta). In addition, in JAM-A-positive cells, motility was enhanced on inactivation of protein kinase Czeta (PKCzeta), which is an inhibitor of GSK-3beta. Although these findings suggested that JAM-A might inhibit GSK-3beta, we found that expression per se of JAM-A did not change the levels of inactive GSK-3beta. Thus, JAM-A expression may regulate effectors of motility that are also downstream of the PKCzeta/GSK-3beta axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions. Notably, all the functional consequences of JAM-A absence were reversed either on treatment with GSK-3beta inhibitors or on transfection of full-length JAM-A, but not on transfection of a JAM-A deletion mutant devoid of the PSD95-Dlg-ZO1-binding residues. Thus, by regulating cytoskeletal and adhesive structures, JAM-A expression prevents cell motility, probably in a PSD95-Dlg-ZO1-dependent manner.

Published
2005
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3. JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling

Author

Fabrizio Orsenigo, Fritz Krombach, Christoph A. Reichel, Elisabetta Dejana, Ruggero Pardi, Monica Fabbri, Maria Rosaria Cera, Markus Rehberg, Cinzia Molendini, Monica Corada, Cera, Mr, Fabbri, M, Molendini, C, Corada, M, Orsenigo, F, Rehberg, M, Reichel, Ca, Krombach, F, Pardi, Ruggero, and Dejana, E.

Subjects
Male, Neutrophils, Uropod, media_common.quotation_subject, education, Integrin, Immunoglobulins, Motility, Uropod retraction, Receptors, Cell Surface, Leukotriene B4, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Animals, Humans, Internalization, Egtazic Acid, Chelating Agents, 030304 developmental biology, media_common, Mice, Knockout, 0303 health sciences, biology, Chemotaxis, Integrin beta1, Cytoplasmic Vesicles, fungi, rap1 GTP-Binding Proteins, Cell migration, Cell Biology, humanities, Cell biology, Mice, Inbred C57BL, N-Formylmethionine Leucyl-Phenylalanine, Integrin alpha M, 030220 oncology & carcinogenesis, biology.protein, Cell Adhesion Molecules, Oligopeptides
Abstract

The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin β1. Clustering of β1 integrin leads to JAM-A co-clustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize β1 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.

Published
2009

4. Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease

Author

Elisabetta Dejana, Alberto Malesci, C. Correale, Andreas Sturm, Cristiano Rumio, Andrea Doni, Silvio Danese, Elena Monica Borroni, Massimo Fantini, Alessandro Repici, Maria Rosaria Cera, Stefania Vetrano, Maria Rescigno, Massimo Locati, Vetrano, S, Rescigno, M, Cera, Mr, Correale, C, Rumio, C, Doni, A, Fantini, M, Sturm, A, Borroni, E, Repici, A, Locati, M, Malesci, A, Dejana, E, and Danese, S

Subjects
Male, Pathology, tight junctions, medicine.medical_treatment, Apoptosis, Inflammatory bowel disease, Mice, Crohn Disease, Cell Movement, Leukocytes, Homeostasis, Intestinal Mucosa, Tight junction, Gastroenterology, apoptosis, Ulcerative colitis, humanities, Cytokine, toll-like receptor-4, cardiovascular system, Cytokines, Tumor necrosis factor alpha, RNA Interference, epithelial barrier, medicine.symptom, medicine.medical_specialty, mice, experimental colitis, education, ischemia-reperfusion injury, Down-Regulation, Immunoglobulins, Inflammation, Receptors, Cell Surface, Biology, Permeability, jam-A, medicine, Animals, Humans, Colitis, Intestinal permeability, Hepatology, pathway, fungi, blockade, medicine.disease, Mice, Mutant Strains, Disease Models, Animal, Colitis, Ulcerative, Cell Adhesion Molecules, Gene Deletion
Abstract

Background & Aims: Junctional adhesion molecule-A (JAM-A) is localized at the tight junctions and controls leukocyte migration into the tissues. However, its functional role in inflammatory bowel disease (IBD) is unexplored. Methods: Control, Crohn's disease (CD), and ulcerative colitis (UC) tissue specimens were studied for JAM-A expression, as well as the colon of mice given dextran sodium sulfate (DSS). Wild-type and JAM-A(-/-), Tie-2-Cre-JAM-A(-/-) (endothelial/hematopoietic-specific JAM inactivation) mice were studied for susceptibility to DSS. Disease activity and colonic inflammation were assessed using a disease activity index histology and endoscopy, and mucosal cytokines were measured by enzyme-linked immunosorbent assay. JAM-A function was investigated by RNA silencing in epithelial cells, and apoptosis was measured. Results: In both CD and UC, as well as in experimental colitis, there is a loss of epithelial. but not endothelial JAM-A expression. Deletion of JAM-A results in a dramatic increase in susceptibility to DSS colitis, as assessed by weight loss, disease activity index, histologic and endoscopic severity, and strikingly high mortality rates. This is not caused by the absence of JAM-A in the endothelial or hematopoietic compartments because Tie-2Cre-JAM-A(-/-) mice are no more susceptible to DSS colitis than wild-type animals. JAM-A(-/-) mice displayed increased intestinal permeability and inflammatory cytokine production, and marked epithelial apoptosis. Silencing of JAM-A in intestinal epithelial cells resulted in increased permeability in vitro. Conclusions: Our results show a nonredundant and novel role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function. RI Locati, Massimo/A-3146-2009 BACKGROUND & AIMS: Junctional adhesion molecule-A (JAM-A) is localized at the tight junctions and controls leukocyte migration into the tissues. However, its functional role in inflammatory bowel disease (IBD) is unexplored. METHODS: Control, Crohn's disease (CD), and ulcerative colitis (UC) tissue specimens were studied for JAM-A expression, as well as the colon of mice given dextran sodium sulfate (DSS). Wild-type and JAM-A(-/-), Tie-2-Cre-JAM-A(-/-) (endothelial/hematopoietic-specific JAM inactivation) mice were studied for susceptibility to DSS. Disease activity and colonic inflammation were assessed using a disease activity index histology and endoscopy, and mucosal cytokines were measured by enzyme-linked immunosorbent assay. JAM-A function was investigated by RNA silencing in epithelial cells, and apoptosis was measured. RESULTS: In both CD and UC, as well as in experimental colitis, there is a loss of epithelial but not endothelial JAM-A expression. Deletion of JAM-A results in a dramatic increase in susceptibility to DSS colitis, as assessed by weight loss, disease activity index, histologic and endoscopic severity, and strikingly high mortality rates. This is not caused by the absence of JAM-A in the endothelial or hematopoietic compartments because Tie-2-Cre-JAM-A(-/-) mice are no more susceptible to DSS colitis than wild-type animals. JAM-A(-/-) mice displayed increased intestinal permeability and inflammatory cytokine production, and marked epithelial apoptosis. Silencing of JAM-A in intestinal epithelial cells resulted in increased permeability in vitro. CONCLUSIONS: Our results show a nonredundant and novel role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function.

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