Elevated CXCL1 expression in gp130-deficient endothelial cells impairs neutrophil migration in mice

Blood. 2013 Nov 28;122(23):3832-42. doi: 10.1182/blood-2012-12-473835. Epub 2013 Sep 30.

Abstract

Neutrophils emigrate from venules to sites of infection or injury in response to chemotactic gradients. How these gradients form is not well understood. Some IL-6 family cytokines stimulate endothelial cells to express adhesion molecules and chemokines that recruit leukocytes. Receptors for these cytokines share the signaling subunit gp130. We studied knockout mice lacking gp130 in endothelial cells. Unexpectedly, gp130-deficient endothelial cells constitutively expressed more CXCL1 in vivo and in vitro, and even more upon stimulation with tumor necrosis factor-α. Mobilization of this increased CXCL1 from intracellular stores to the venular surface triggered β2 integrin-dependent arrest of neutrophils rolling on selectins but impaired intraluminal crawling and transendothelial migration. Superfusing CXCL1 over venules promoted neutrophil migration only after intravenously injecting mAb to CXCL1 to diminish its intravascular function or heparinase to release CXCL1 from endothelial proteoglycans. Remarkably, mice lacking gp130 in endothelial cells had impaired histamine-induced venular permeability, which was restored by injecting anti-P-selectin mAb to prevent neutrophil rolling and arrest. Thus, excessive CXCL1 expression in gp130-deficient endothelial cells augments neutrophil adhesion but hinders migration, most likely by disrupting chemotactic gradients. Our data define a role for endothelial cell gp130 in regulating integrin-dependent adhesion and de-adhesion of neutrophils during inflammation.

Publication types

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

MeSH terms

  • Animals
  • Capillary Permeability / physiology
  • Cell Adhesion / physiology
  • Cell Movement / physiology
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism*
  • Cytokine Receptor gp130 / deficiency*
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / physiology
  • Endothelial Cells / physiology*
  • Inflammation / physiopathology
  • Leukocyte Rolling / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / physiology*
  • P-Selectin / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / physiology
  • Up-Regulation
  • Venules / physiology

Substances

  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Il6st protein, mouse
  • P-Selectin
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Cytokine Receptor gp130