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Adhesion molecule-dependent mechanisms regulate the rate of macrophage clearance during the resolution of peritoneal
Geoffrey John Bellingan1, Ping Xu, Helen Cooksley
1Centre for Respiratory Research, Rayne Institute, University College London, University Street, London WC1E 6JJ, United Kingdom. g.bellingan@ucl.ac.uk
Abstract:
Macrophage clearance is essential for the resolution of inflammation. Much is known about how monocytes enter the inflammatory site but little is known about how resultant macro-phages are cleared. We have previously demonstrated that macrophage clearance from resolving peritonitis occurs by emigration into draining lymphatics rather than local apoptosis. We now examine mechanisms for this process, in particular by evaluating the hypothesis that modulation of adhesion interactions between macrophages and cells lining the lymphatics regulates the rate of macrophage clearance. We demonstrate in vivo that macrophages adhere specifically to mesothelium overlying draining lymphatics and that their emigration rate is regulated by the state of macrophage activation. We observed that macrophage-mesothelial adhesion is Arg-Gly-Asp (RGD) sensitive and partially mediated by very late antigen (VLA)-4 and VLA-5 but not alpha(v) or beta(2) integrins. Moreover, macrophage clearance into lymphatics can be blocked in vivo by RGD peptides and VLA-4 and VLA-5 but not beta(2) blocking antibodies. This is the first evidence that macrophage emigration from the inflamed site is controlled and demonstrates that this is exerted through specific adhesion molecule regulation of macrophage-mesothelial interactions. It highlights the importance of adhesion molecules governing entry of cells into the lymphatic circulation, thus opening a new avenue for manipulating the resolution of inflammation.
Insights
Macrophage clearance from inflammation relies on specific adhesion molecules, not just apoptosis. Targeting these interactions, like very late antigen (VLA)-4 and VLA-5, controls macrophage exit into lymphatics for resolving inflammation.
Area of Science:
- Immunology
- Cell Biology
- Physiology
Background:
- Macrophage clearance is crucial for resolving inflammation.
- Mechanisms of macrophage emigration from inflammatory sites are poorly understood.
- Previous work showed macrophages leave via lymphatics, not apoptosis.
Purpose of the Study:
- To investigate the mechanisms regulating macrophage clearance from inflammatory sites.
- To test if adhesion interactions between macrophages and lymphatic endothelial cells control clearance rate.
- To identify specific adhesion molecules involved in macrophage emigration.
Main Methods:
- In vivo studies in a peritonitis model.
- Evaluation of macrophage adherence to lymphatic mesothelium.
- Assessment of the role of specific integrins (VLA-4, VLA-5, alpha(v), beta(2)) and Arg-Gly-Asp (RGD) sequences.
- In vivo blockade experiments using RGD peptides and blocking antibodies.
Main Results:
- Macrophages specifically adhere to mesothelium overlying draining lymphatics.
- Macrophage emigration rate is regulated by the macrophage activation state.
- Adhesion is Arg-Gly-Asp (RGD) sensitive and involves very late antigen (VLA)-4 and VLA-5 integrins.
- Macrophage clearance into lymphatics can be blocked by RGD peptides and antibodies against VLA-4 and VLA-5.
Conclusions:
- Macrophage emigration from inflamed tissues is a controlled process.
- Specific adhesion molecules regulating macrophage-mesothelial interactions govern this emigration.
- Targeting these adhesion molecules offers a novel strategy for manipulating inflammatory resolution by controlling lymphatic entry.