Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1

Ronen Sumagin, Julia M. Kuebel, Ingrid H. Sarelius

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Activated neutrophils interacting with the vessel wall can alter vascular permeability to macromolecules such as albumin via release of various secretion products that induce changes in the endothelial monolayer. In the current work we used cremaster microvessels of anesthetized mice to show that, in addition to this paracrine mechanism, leukocyte ligation of endothelial ICAM-1 directly activates endothelial cell (EC) signaling, altering EC permeability to albumin [i.e., solute permeability (P s)]. We show that antibody cross-linking of surface ICAM-1 in intact microvessels is sufficient to increase P s even in the absence of interacting leukocytes. Unstimulated arterioles do not support leukocyte-EC interactions, but despite this, antibody ligation of ICAM-1 in these vessels induced a twofold increase in P s. Similarly, in venules that were depleted of interacting neutrophils, Ps was decreased to below resting levels and was restored by ligation of ICAM-1. Use of function-blocking antibodies to separately block leukocyte rolling or adhesion under unstimulated or TNF-α-activated conditions established that both rolling and adhered leukocytes contribute to P s regulation in situ. Both rolling and adhesion activated EC-dependent signaling mechanisms that increased P s. ICAM-1 ligation with primary antibody alone or primary followed by secondary antibodies showed that regulation of P s is directly dependent on the degree of ICAM-1 clustering. Under physiological versus inflamed conditions, respectively, this ICAM-1 clustering-dependent regulation of P s switches from PKC dependent and Src independent to Src dependent and PKC independent. This study thus identifies a new mechanism by which antiadhesion treatment may constitute a potential therapy for tissue edema.

Original languageEnglish (US)
Pages (from-to)C804-C813
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number4
DOIs
StatePublished - Oct 2011

Keywords

  • Adhesion molecules
  • Leukocyte-endothelial signaling
  • Microvessel barrier function

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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