MCP-1 and attenuation of the foreign body response

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Biomaterials elicit a distinct inflammatory response leading to the formation of destructive foreign body giant cells (FBGC) that participate in the encapsulating foreign body response (FBR). We have described the participation of the chemokine MCP1 in the formation of FBGC and fibrotic encapsulation; the latter in a tissue- specific manner. Specifically, we found that MCP1 is critical for FBGC formation in both subcutaneous (SC) and intraperitoneal (IP) implantation models and for fibrosis only in the latter. Our findings prompted us to investigate the activation phenotype of WT and MCP1 KO macrophages in the context of the FBR IP. In preliminary studies, we have discovered a reduction in the levels of TNF-? and low activation of the NF?B pathway in vitro and in vivo. Moreover, these defects were associated with reduced levels of TGF-ß and attenuated fibrosis. Therefore, our findings suggest that MCP1 is a critical determinant of macrophage polarization/activation in the FBR. To gain greater inside into the mechanism of biomaterial-induced macrophage activation and fusion, we initiated high throughput analysis of cDNA and micro inhibitory RNA (miRNA) arrays with a focus on identifying genes and miRNAs that are differentially regulated in WT and MCP1 macrophages. In addition, we have explored macrophage signaling by focusing on activation of kinases and preliminary studies indicate a defect in ERK1/2 activation in MCP1 KO macrophages. In this application, we propose studies to explore and exploit macrophage activation and identify mechanistic links between this process and the progression of the FBR in various tissues. In addition, we aim to expand and translate some of our findings into bioengineering approaches that should provide proof-of-principle for the modulation of macrophage phenotype as a strategy to attenuate the FBR. Accordingly, the specific aims of this application are: 1) to test the hypothesis the MCP1-specific signaling modulates the function of biomaterial-adherent macrophages; 2) to test the hypothesis that biomaterial-induced macrophage activation is a critical determinant of implant fibrosis; and 3) to test the hypothesis that biomaterial-induced macrophage activation and/or fusion is regulated by specific miRNAs.