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The FBR is characterized by a subset of multinucleated giant cells (MGCs) formed by macrophage fusion, the foreign body giant cells (FBGCs), accompanied by inflammatory cytokines, matrix deposition, and eventually deleterious fibrotic implant encapsulation. Despite efforts to improve biocompatibility, implant-induced FBR persists, compromising the utility of devices and making efforts to control the FBR imperative for long-term function. Controlling macrophage fusion in FBGC formation presents a logical target to prevent implant failure, but the actual contribution of FBGCs to FBR-induced damage is controversial. CD13 is a molecular scaffold, and in vitro induction of CD13KO bone marrow progenitors generates many more MGCs than the wild type, suggesting that CD13 regulates macrophage fusion. In the mesh implant model of FBR, CD13KO mice produced significantly more peri-implant FBGCs with enhanced TGF-\u03b2 expression and increased collagen deposition versus the wild type. Prior to fusion, increased protrusion and microprotrusion formation accompanies hyperfusion in the absence of CD13. Expression of fusogenic proteins driving cell\u2013cell fusion was aberrantly sustained at high levels in CD13KO MGCs, which we show is due to a novel CD13 function, to our knowledge, regulating ubiquitin\/proteasomal protein degradation. We propose CD13 as a physiologic brake limiting aberrant macrophage fusion and the FBR, and it may be a novel therapeutic target to improve the success of implanted medical devices. Furthermore, our data directly implicate FBGCs in the detrimental fibrosis that characterizes the FBR.<\/jats:p>","DOI":"10.4049\/jimmunol.2300688","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T09:47:50Z","timestamp":1703670470000},"page":"663-676","source":"Crossref","is-referenced-by-count":5,"title":["The Implant-Induced Foreign Body Response Is Limited by CD13-Dependent Regulation of Ubiquitination of Fusogenic Proteins"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5090-1275","authenticated-orcid":false,"given":"Mallika","family":"Ghosh","sequence":"first","affiliation":[{"name":"Centers for Vascular Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2591-8748","authenticated-orcid":false,"given":"Fraser","family":"McGurk","sequence":"additional","affiliation":[{"name":"Centers for Vascular Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Norris","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Dong","sequence":"additional","affiliation":[{"name":"Centers for Vascular Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreenidhi","family":"Nair","sequence":"additional","affiliation":[{"name":"Centers for Vascular Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2674-1605","authenticated-orcid":false,"given":"Evan","family":"Jellison","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Murphy","sequence":"additional","affiliation":[{"name":"Centers for Vascular Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1123-6508","authenticated-orcid":false,"given":"Rajkumar","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4590-4671","authenticated-orcid":false,"given":"Linda H","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Centers for Vascular Biology, University of Connecticut Medical School , Farmington, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"2025020405443199200_r1","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1016\/j.ajpath.2011.01.045","article-title":"Lack of TNF-\u03b1-induced MMP-9 production and abnormal E-cadherin redistribution associated with compromised fusion in MCP-1-null macrophages","volume":"178","author":"Skokos","year":"2011","journal-title":"Am. 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