Document Detail

Foreign body giant cell formation is preceded by lamellipodia formation and can be attenuated by inhibition of Rac1 activation.
MedLine Citation:
PMID:  17556592     Owner:  NLM     Status:  MEDLINE    
Macrophages that are recruited to the site of implanted biomaterials undergo fusion to form surface-damaging foreign body giant cells. Exposure of peripheral blood monocytes to interleukin-4 can recapitulate the fusion process in vitro. In this study, we used interleukin-4 to induce multinucleation of murine bone marrow-derived macrophages and observed changes in cell shape, including elongation and lamellipodia formation, before fusion. Because cytoskeletal rearrangements are regulated by small GTPases, we examined the effects of inhibitors of Rho kinase (Y-32885) and Rac activation (NSC23766) on fusion. Y-32885 did not prevent cytoskeletal changes or fusion but limited the extent of multinucleation. NSC23766, on the other hand, inhibited lamellipodia formation and fusion in a dose-dependent manner. In addition, we found that in control cells, these changes were preceded by Rac1 activation. However, NSC23766 did not block the uptake of polystyrene microspheres. Likewise, short interfering RNA knockdown of Rac1 limited fusion without limiting phagocytosis. Thus, phagocytosis and fusion can be partially decoupled based on their susceptibility to NSC23766. Furthermore, poly(ethylene-co-vinyl acetate) scaffolds containing NSC23766 attenuated foreign body giant cell formation in vivo. These observations suggest that targeting Rac1 activation could protect biomaterials without compromising the ability of macrophages to perform beneficial phagocytic functions at implantation sites.
Steven M Jay; Eleni Skokos; Farah Laiwalla; Marie-Marthe Krady; Themis R Kyriakides
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-06-07
Journal Detail:
Title:  The American journal of pathology     Volume:  171     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-27     Completed Date:  2007-09-13     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  632-40     Citation Subset:  AIM; IM    
Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut 06519, USA.
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MeSH Terms
Aminoquinolines / pharmacokinetics,  pharmacology
Bone Marrow Cells / drug effects,  metabolism
Cell Shape / drug effects
Chemokine CCL2 / genetics,  metabolism
Dose-Response Relationship, Drug
Drug Implants
Giant Cells, Foreign-Body / drug effects,  metabolism*
Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
Interleukin-4 / pharmacology
Macrophages / drug effects,  metabolism
Mice, Inbred C57BL
Mice, Knockout
Monomeric GTP-Binding Proteins / antagonists & inhibitors,  genetics,  metabolism
Phagocytosis / drug effects
Pseudopodia / metabolism*
Pyrimidines / pharmacokinetics,  pharmacology
RNA Interference
RNA, Small Interfering / genetics
rac1 GTP-Binding Protein / antagonists & inhibitors,  genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Aminoquinolines; 0/Ccl2 protein, mouse; 0/Chemokine CCL2; 0/Drug Implants; 0/NSC 23766; 0/Pyrimidines; 0/RNA, Small Interfering; 207137-56-2/Interleukin-4; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor; EC GTP-Binding Proteins; EC GTP-Binding Protein

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