# The role of beta 2 integrins in macrophage fusion

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2021 · $479,666

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 10082459
- **Project number:** 5R01HL063199-20
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Tatiana P Ugarova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $479,666
- **Award type:** 5
- **Project period:** 1999-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10082459

## Citation

> US National Institutes of Health, RePORTER application 10082459, The role of beta 2 integrins in macrophage fusion (5R01HL063199-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10082459. Licensed CC0.

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