title: Endothelial reticulon-4B (Nogo-B) regulates ICAM-1-mediated leukocyte transmigration and acute inflammation.
abstract: The reticulon (Rtn) family of proteins are localized primarily to the endoplasmic reticulum (ER) of most cells. The Rtn-4 family, (aka Nogo) consists of 3 splice variants of a common gene called Rtn-4A, Rtn-4B, and Rtn-4C. Recently, we identified the Rtn-4B (Nogo-B) protein in endothelial and smooth muscle cells of the vessel wall, and showed that Nogo-B is a regulator of cell migration in vitro and vascular remodeling and angiogenesis in vivo. However, the role of Nogo-B in inflammation is still largely unknown. In the present study, we use 2 models of inflammation to show that endothelial Nogo-B regulates leukocyte transmigration and intercellular adhesion molecule-1 (ICAM-1)-dependent signaling. Mice lacking Nogo-A/B have a marked reduction in neutrophil and monocyte recruitment to sites of inflammation, while Nogo-A/B(-/-) mice engrafted with wild-type (WT) bone marrow still exhibit impaired inflammation compared with WT mice engrafted with Nogo-A/B(-/-) bone marrow, arguing for a critical role of host Nogo in this response. Using human leukocytes and endothelial cells, we show mechanistically that the silencing of Nogo-B with small interfering RNA (siRNA) impairs the transmigration of neutrophils and reduces ICAM-1-stimulated phosphorylation of vascular endothelial-cell cadherin (VE-cadherin). Our results reveal a novel role of endothelial Nogo-B in basic immune functions and provide a key link in the molecular network governing endothelial-cell regulation of diapedesis.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, CT, USA.
authors.forename: Annarita
authors.initials: A
authors.lastname: Di Lorenzo
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Manes
authors.forename: Alberto
authors.initials: A
authors.lastname: Davalos
authors.forename: Paulette L
authors.initials: PL
authors.lastname: Wright
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D015820:Cadherins / Q000502:physiology; D002351:Carrageenan / Q000633:toxicity; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology / Q000502:physiology*; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D000070798:Nogo Proteins; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D002351:Carrageenan; D051418:Focal Adhesion Kinase 2; D018799:Intercellular Adhesion Molecule-1; D009185:Myelin Proteins; D000070798:Nogo Proteins; D034741:RNA, Small Interfering; D019061:src-Family Kinases; D000099152:Cadherin 5; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse