Abstract
Angiopoietins are a family of growth factors that are ligands for the tyrosine kinase receptor, Tie2. Angiopoietin 1 (Ang-1) is agonistic for Tie2, plays a key role in blood vessel maturation and stability and has been shown to possess anti-inflammatory properties. However, Tie2 expression has been demonstrated on human neutrophils and the observation that neutrophils migrate in response to Ang-1 in vitro has confounded research into its exact role in inflammation as well as its potential use as a therapeutic agent. We used a mouse model of peritoneal neutrophilic inflammation to determine if Ang-1 could stimulate neutrophil migration in vivo. Tie2 expression was demonstrated on mouse neutrophils. In addition, recombinant human Ang-1 induced significant chemotaxis of isolated mouse neutrophils in a Tie2- and CD18-dependent manner. Subsequently, co-immunoprecipitation of Ang-1 and CD18 demonstrated their interaction. Intraperitoneal injection of an engineered angiopoietin-1, MAT.Ang-1, induced significant neutrophil migration into the peritoneum and a significant increase in the levels of CCL4 in peritoneal lavage fluid. Depletion of resident peritoneal macrophages prior to, or concomitant injections of an anti-CCL4 antibody with MAT.Ang-1 resulted in a significant reduction in neutrophil recruitment. These data indicate a pro-inflammatory role for Ang-1 with respect to neutrophil recruitment.
Highlights
The inflammatory process is of great importance in host defence but is a major contributor to numerous disease processes[1]
We demonstrate that mouse neutrophils express Tie[2] and migrate towards recombinant human Angiopoietin 1 (Ang-1) in vitro in a Tie[2] and CD18-dependent manner
Flow cytometry analysis, using Ly6G positivity to gate on the neutrophil population in lysed mouse whole blood, demonstrated expression of Tie[2] on mouse neutrophils (Fig. 1A and B); as previously shown, Tie[2] expression was found on monocytes as previously described[19] but we were unable to detect its expression on lymphocytes (Data not shown)
Summary
The inflammatory process is of great importance in host defence but is a major contributor to numerous disease processes[1]. Demonstrated that Ang-1 inhibits VEGF-induced expression of endothelial cell adhesion molecules ICAM-1, VCAM-1 and E-selectin[10], which are involved in recruiting leukocytes in inflammatory responses. Ang-1 has been heralded as a potential novel compound for treatment of inflammatory diseases[17, 18], studies demonstrating the expression of Tie[2] on neutrophils and their responsiveness to angiopoietins have highlighted the need for further investigation. The stable MAT.Ang-1 induces neutrophil migration and cytokine release in vivo These novel data demonstrate that Ang-1 can act in a pro-inflammatory manner, in vitro, and in vivo
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