Endothelial reticulon-4B (Nogo-B) regulates ICAM-1-mediated leukocyte transmigration and acute inflammation

Blood. 2011 Feb 17;117(7):2284-95. doi: 10.1182/blood-2010-04-281956. Epub 2010 Dec 23.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / physiology
  • Cadherins / physiology
  • Carrageenan / toxicity
  • Cell Movement / physiology
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Focal Adhesion Kinase 2 / metabolism
  • Humans
  • In Vitro Techniques
  • Inflammation / etiology*
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Intercellular Adhesion Molecule-1 / physiology*
  • Leukocytes / pathology
  • Leukocytes / physiology*
  • Macrophages / pathology
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Congenic
  • Mice, Knockout
  • Monocytes / pathology
  • Monocytes / physiology
  • Myelin Proteins / antagonists & inhibitors
  • Myelin Proteins / deficiency
  • Myelin Proteins / genetics
  • Myelin Proteins / physiology*
  • Neutrophils / pathology
  • Neutrophils / physiology
  • Nogo Proteins
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • src-Family Kinases / metabolism

Substances

  • Antigens, CD
  • Cadherins
  • Myelin Proteins
  • Nogo Proteins
  • RNA, Small Interfering
  • RTN4 protein, human
  • Rtn4 protein, mouse
  • cadherin 5
  • Intercellular Adhesion Molecule-1
  • Carrageenan
  • Focal Adhesion Kinase 2
  • src-Family Kinases