title: Nanoparticle delivery of miR-223 to attenuate macrophage fusion.
abstract: The foreign body response (FBR) begins with injury acquired during implantation of a biomaterial (BM) and is detrimental due to the eventual encapsulation of the implant. Fusion of macrophages to form foreign body giant cells (FBGC), a hallmark of the FBR, is the consequence of a multistep mechanism induced by interleukin (IL)-4 that includes the acquisition of a fusion competent state and subsequent cytoskeletal rearrangements. However, the precise mechanism, regulation, and interplay among molecular mediators to generate FBGCs are insufficiently understood. Seeking novel mediators of fusion that might be regulated at the post-transcriptional level, we examined the role of microRNAs (miRs) in this process. A miR microarray was screened and identified miR-223 as a negative regulator of macrophage fusion. In addition, transfection of primary macrophages with a mir-223 mimic attenuated IL-4-induced fusion. Furthermore, miR-223 KO mice and mir-223 deficient cells displayed increased fusion in vivo and in vitro, respectively. Finally, we developed a method for in vivo delivery of miR-223 mimic utilizing PLGA nanoparticles, which inhibited FBGC formation in a biomaterial implant model. Our results identify miR-223 as a negative regulator of fusion and demonstrate miR-223 mimic-loaded nanoparticles as a therapeutic inhibitor of macrophage fusion.
authors.affiliation: Department of Genetics, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA.
authors.forename: Laura Beth
authors.initials: LB
authors.lastname: Moore
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sawyer
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Saucier-Sawyer
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA. Electronic address: themis.kyriakides@yale.edu.
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D000818:Animals; D002459:Cell Fusion; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D015743:Giant Cells, Foreign-Body / Q000166:cytology / Q000378:metabolism*; D019344:Lactic Acid / Q000737:chemistry; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D053758:Nanoparticles / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Biomaterial; Foreign body giant cell; Macrophage fusion; Nanoparticle; microRNA