The Implant-Induced Foreign Body Response is Limited by CD13-Dependent Regulation of Ubiquitination of Fusogenic Proteins

Abstract

Implanted medical devices from artificial heart valves, arthroscopic joints to implantable sensors often induce a Foreign Body Response (FBR), a form of chronic inflammation resulting from the inflammatory reaction to a persistent foreign stimulus. 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 WT, suggesting CD13 regulates macrophage fusion. Moreover, in the mesh implant model of FBR, CD13KO mice produced significantly more peri-implant FBGCs with enhanced TGF{beta} expression and increased collagen deposition vs. WT. Pre-fusion, increased protrusion and microprojection formation accompanies hyperfusion in the absence of CD13. Expression of fusogenic proteins driving cell-cell fusion was aberrantly sustained at high levels in CD13KO MGCs, which we show is due to a novel CD13 function, regulating ubiquitin/proteasomal protein degradation. By controlling protein degradation, CD13 becomes a physiologic brake preventing aberrant macrophage fusion and may be a novel therapeutic target to improve success of implanted medical devices. Furthermore, our data directly implicates FBGCs in the detrimental fibrosis that characterizes the FBR.