# Targeting the Proinflammatory Activity of Integrin Mac-1 for Treatment of Atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $468,174

## Abstract

A major player in the development of inflammatory diseases, such as atherosclerosis, is vascular
macrophages, which are primarily derived from infiltrating monocytes in an integrin-dependent process. Mac-1
(CD11b/CD18, αMβ2 or CR3), a major integrin expressed on macrophages, is generally considered as a
proinflammatory receptor. Surprisingly, we find that Mac-1 deficiency on an LDLR-/- background exacerbates
atherosclerosis, which contradicts published observations obtained using bone marrow transplantation
approaches. To resolve this discrepancy, we performed reciprocal bone marrow transplantation experiments,
and our new data agree with the published results. Unexpectedly, they implicate the existence of a subset of
Mac-1+ resident cells with atheroprotective functions. Also contradicting the paradigm of Mac-1 being a
proinflammatory receptor, we discovered that Mac-1 possesses a novel anti-inflammatory activity (J Exp Med
2007). In support of our original finding, genome-wide association studies have linked loss-of-function Mac-1
variants in human population to a greater risk of lupus, an autoimmune disease that correlates with accelerated
atherosclerosis. Thus, Mac-1 appears to both promote and inhibit the development of inflammatory diseases;
however, the molecular mechanism that confers Mac-1 with these diametrically opposing activities is unknown.
In our preliminary studies, we screened several existing homolog-scanning Mac-1 mutants and identified a
novel Mac-1 variant (D289A290→KH) that abolishes Mac-1’s proinflammatory activity without compromising its
anti-inflammatory functions. Subsequently, we generated a knock-in mouse, Mac-1NA, using the CRISPR/Cas9
technology, in which the homologous residues (N289A290) of murine Mac-1 were mutated. Our preliminary study
revealed that Mac-1-/- and Mac-1NA mice exhibit opposite patterns of inflammatory responses in vitro and in
vivo. Based on these exciting preliminary data, we hypothesize that Mac-1 expressed on a subset of aortic
resident cells plays an atheroprotective role by suppressing vascular inflammation. To test our hypothesis, we
generated a GFP-coupled Mac-1flox mouse, which was subsequently crossed with the tamoxifen-inducible
CX3CR1-CreERT2 mouse. Using this novel CX3CR1-CreERT2;Mac-1flox strain, we successfully tagged resident
macrophages but not monocytes with GFP and simultaneously deleted their Mac-1 expression. We propose to
use this novel mouse strain to identify the atheroprotective subset of Mac-1-expressing resident cells. We will
also establish molecular mechanisms underlying the differential ability of Mac-1-/- and Mac-1NA to regulate
macrophage proliferation, intracellular signaling, and foam cell differentiation during the development of
atherosclerosis. Finally, we will investigate novel strategies to selectively target Mac-1’s proinflammatory
functions and test their effectiveness to reduce atherosclerosis. Completion of this project will provide new
insights into the ...

## Key facts

- **NIH application ID:** 10126050
- **Project number:** 5R01HL142909-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** LI ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,174
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126050

## Citation

> US National Institutes of Health, RePORTER application 10126050, Targeting the Proinflammatory Activity of Integrin Mac-1 for Treatment of Atherosclerosis (5R01HL142909-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10126050. Licensed CC0.

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