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Angiopoietin-1 enhances neutrophil chemotaxis in vitro and migration in vivo through interaction with CD18 and release of CCL4.

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.

SUBMITTER: Burnett A

PROVIDER: S-EPMC5443761 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Angiopoietin-1 enhances neutrophil chemotaxis in vitro and migration in vivo through interaction with CD18 and release of CCL4.

Burnett Amanda A Gomez Ingrid I De Leon David Davila DD Ariaans Mark M Progias Pavlos P Kammerer Richard A RA Velasco Guillermo G Marron Marie M Hellewell Paul P Ridger Victoria V

Scientific reports 20170524 1

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 ...[more]

PMID: 28539655

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Project description:Neutrophils are always surrounded by/interacting with other components of the immune system; however, the current mechanistic understanding of neutrophil function is largely based on how neutrophils respond to a single chemical signal in a simplified environment. Such approaches are unable to recapitulate the in vivo microenvironment; thus, cell behavior may not fully represent the physiological behavior. Herein, we exploit a microfluidic model of the complex in vivo milieu to investigate how cell-cell interactions influence human neutrophil migration and surface marker expression. Neutrophil migration against a bacterially derived chemoattractant (formyl-met-leu-phe, fMLP), with and without preactivation by interleukins (interleukin-2 or interleukin-6), was evaluated in the presence and absence of endothelial support cells. Preactivation by interleukins or interaction with endothelial cells resulted in altered migration rates compared to naïve neutrophils, and migration trajectories deviated from the expected movement toward the fMLP signal. Interestingly, interaction with both interleukins and endothelial cells simultaneously resulted in a slight compensation in the deviation-on endothelial cells, 34.4% of untreated neutrophils moved away from the fMLP signal, while only 15.2 or 22.2% (interleukin-2-or interleukin-6-activated) of preactivated cells moved away from fMLP. Neutrophils interacting with interleukins and/or endothelial cells were still capable of prioritizing the fMLP signal over a competing chemoattractant, leukotriene B4 (LTB4). Fluorescence imaging of individual human neutrophils revealed that neutrophils treated with endothelial-cell-conditioned media showed up-regulation of the surface adhesion molecules cluster determinant 11b and 66b (CD11b and CD66b) upon stimulation. On the other hand, CD11b and CD66b down-regulation was observed in untreated neutrophils. These results leverage single cell analysis to reveal that the interaction between neutrophils and endothelial cells is involved in surface marker regulation and thus chemotaxis of neutrophils. This study brings new knowledge about neutrophil chemotaxis in the context of cell-to-cell communications, yielding both fundamental and therapeutically relevant insight.

Dataset Information

Angiopoietin-1 enhances neutrophil chemotaxis in vitro and migration in vivo through interaction with CD18 and release of CCL4.

Publications

Angiopoietin-1 enhances neutrophil chemotaxis in vitro and migration in vivo through interaction with CD18 and release of CCL4.

Similar Datasets

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