Macrophage fusion resulting in the formation of multinucleated giant cells (MGCs) accompanies a variety of maladies associated with chronic inflammation, including the foreign body response (FBR) elicited by implanted biomaterials. Despite the long history of research on FBR, the molecular and cellular mechanisms of macrophage fusion, an event central to the long-term failure of implanted prosthetic vascular grafts and other medical devices, remain poorly understood. In our preliminary studies using in vivo implantation model, we found that the formation of MGCs and granulation tissue, which develops around the implant and is a precursor of the undesirable fibrotic cap, was almost completely abolished in fibrinogen-deficient mice. Surprisingly, the number of MGCs formed on biomaterials implanted into Mac-1-deficient mice was greater than in wild-type mice and the thickness of granulation tissue was larger. We hypothesize that macrophage fusion on biomaterials critically depends on the deposited fibrin(ogen) matrix and the absence of Mac-1, through the alteration of adhesive properties of macrophages, exacerbates the FBR.
Specific Aim 1 is to test this hypothesis. Using a mouse model of biomaterial implantation and gene-targeted mice, we will perform systematic analyses of the early and late stages of FBR and determine the M1/M2 phenotype of MGCs derived from wild-type and Mac-1-deficient macrophages. Using nanotechnology approaches we will characterize the adhesive and mechanical properties of fibrin(ogen) matrices deposited on biomaterials in wild-type and Mac-1-deficient mice.
Specific Aim 2 will characterize previously unrecognized actin- based zipper-like structures (ZLS) that form between MGCs on implanted biomaterials. We developed an in vitro model that reproduces the formation of ZLS and demonstrated that the intercellular space within ZLS is filled with junctional proteins E-cadherin and nectin-2. We hypothesize that MGCs form epithelial-like junctions that aid the MGC survival. Taking advantage of technological innovations including a microfluidic chamber that allows the precise dissection of ZLS followed by proteomics analyses, high-resolution microscopy, live cell imaging and mice with myeloid cell-specific KO of E- cadherin and other components of junctions, we will determine the composition of ZLS and their role in the FBR.
Specific Aim 3 is to determine the role of authentic fusogenic proteins syncytins in macrophage fusion. Based on our finding that macrophage fusion is initiated by an actin-based protrusion, we will use knockdown experiments, EM and video microscopy to test the hypothesis that a fusion-competent protrusion at the leading edge of a donor macrophage contains syncytins. Overalls, these studies will define the novel biology of macrophage fusion and characterize new mechanisms that have the potential to modulate the FBR.

Public Health Relevance

Macrophage fusion resulting in the formation of destructive multinucleated giant cells has been known for decades to accompany a variety of maladies associated with chronic inflammation, including the long-term failure of implanted prosthetic vascular grafts and other medical devices. We establish here that the interaction between plasma protein fibrin(ogen) adsorbed on the surface of implanted biomaterials and its receptor integrin Mac-1 drives macrophage fusion and also identify previously unrecognized actin-based structures in multinucleated giant cells, whose function is unknown. The present proposal employs novel in vivo and in vitro systems to elucidate the mechanisms and functional consequences of macrophage fusion on implanted biomaterials.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Intercellular Interactions Study Section (ICI)
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Ochocinska, Margaret J
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Arizona State University-Tempe Campus
Other Basic Sciences
Schools of Arts and Sciences
United States
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Lishko, Valeryi K; Yakubenko, Valentin P; Ugarova, Tatiana P et al. (2018) Leukocyte integrin Mac-1 (CD11b/CD18, ?M?2, CR3) acts as a functional receptor for platelet factor 4. J Biol Chem 293:6869-6882
Faust, James J; Christenson, Wayne; Doudrick, Kyle et al. (2017) Development of fusogenic glass surfaces that impart spatiotemporal control over macrophage fusion: Direct visualization of multinucleated giant cell formation. Biomaterials 128:160-171
Shen, Di; Podolnikova, Nataly P; Yakubenko, Valentin P et al. (2017) Pleiotrophin, a multifunctional cytokine and growth factor, induces leukocyte responses through the integrin Mac-1. J Biol Chem 292:18848-18861
Podolnikova, Nataly P; Kushchayeva, Yevgeniya S; Wu, YiFei et al. (2016) The Role of Integrins ?M?2 (Mac-1, CD11b/CD18) and ?D?2 (CD11d/CD18) in Macrophage Fusion. Am J Pathol 186:2105-2116
Lishko, Valeryi K; Moreno, Benjamin; Podolnikova, Nataly P et al. (2016) Identification of Human Cathelicidin Peptide LL-37 as a Ligand for Macrophage Integrin ?M?2 (Mac-1, CD11b/CD18) that Promotes Phagocytosis by Opsonizing Bacteria. Res Rep Biochem 2016:39-55
Tsen, Shaw-Wei D; Kibler, Karen; Jacobs, Bert et al. (2016) Selective photonic disinfection of cell culture using a visible ultrashort pulsed laser. IEEE J Sel Top Quantum Electron 22:
Owaynat, Hadil; Yermolenko, Ivan S; Turaga, Ramya et al. (2015) Deposition of fibrinogen on the surface of in vitro thrombi prevents platelet adhesion. Thromb Res 136:1231-9
Safiullin, Roman; Christenson, Wayne; Owaynat, Hadil et al. (2015) Fibrinogen matrix deposited on the surface of biomaterials acts as a natural anti-adhesive coating. Biomaterials 67:151-9
Podolnikova, Nataly P; Podolnikov, Andriy V; Haas, Thomas A et al. (2015) Ligand recognition specificity of leukocyte integrin ?M?2 (Mac-1, CD11b/CD18) and its functional consequences. Biochemistry 54:1408-20
Podolnikova, Nataly P; Brothwell, Julie A; Ugarova, Tatiana P (2015) The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (?M?2, CD11b/CD18). Mol Pain 11:33

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