# Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $415,135

## Abstract

Leakage of blood fibrinogen into the central nerve system and its conversion into reactive fibrin plays a key role
in many neurological diseases, including multiple sclerosis (MS), a neuroinflammatory disease. Fibrin
stimulates the proinflammatory activity of macrophages and microglia by binding to the integrin receptor
CD11b/CD18 (Mac-1; αMβ2). However, this proinflammatory paradigm of CD11b/CD18 is complicated by our
surprising discovery that CD11b/CD18 possesses anti-inflammatory properties in several mouse models of
inflammatory diseases. Indeed, independent genome-wide association studies have linked loss-of-function
variants of human CD11b to increased risks of autoimmune systemic lupus erythematosus. The molecular
mechanism by which ligand binding property of CD11b confers macrophages/microglia with distinct
inflammatory activities is unknown. The overall goal of this project is two-fold: (1) to determine the molecular
basis by which CD11b/CD18 ligand binding confers macrophages and microglia with different inflammatory
properties and (2) to identify specific leukocyte subsets that mediate the pathological or beneficial functions of
CD11b/CD18 in MS. In our preliminary studies, we discovered a novel CD11b mutant, CD11bKH, that is
defective in fibrin binding. Knock-in mice expressing CD11bKH exhibited normal macrophage infiltration but
reduced proinflammatory activity in vivo. Using a mouse model of progressive MS, we found that CD11bKH
mice developed early signs of disease but could spontaneously reverse disease progression, a unique ability
not observed in wild-type or CD11b-deficient mice. Our bone marrow transplantation experiments further
demonstrated that CD11b on bone marrow-derived cells and resident microglia play distinct roles in the
pathogenesis of MS. Based on these exciting preliminary results, we hypothesize that CD11b/CD18
modulates the pathogenesis of MS in a ligand-dependent and cell type-specific manner. To test this hypothesis,
we will determine the ability of CD11b mutants including CD11bKH to bind its various protein ligands associated
with MS. We will also identify key signaling pathways responsible for the CD11b/CD18-fibrin-initiated
proinflammatory activities (Aim 1). We will next determine the mechanism by which CD11b/CD18 modulates
disease progression and remission. Importantly, we will inactivate CD11b on bone marrow-derived cells or
resident microglia at specific stages of disease development using our newly generated CD11b-floxed mice
and determine their impact on disease development (Aim 2). Finally, we will investigate whether disrupting the
CD11b/CD18-fibrin pathway will enhance anti-CD20-induced antigen-specific immunosuppression (Aim 3).
Completion of this project will fill the gap in our knowledge regarding the mechanism by which CD11b/CD18
ligand binding dictates its inflammatory properties. Importantly, given that ocrelizumab (a humanized anti-CD20
mAb) is the only FDA-approved treatment for primary pro...

## Key facts

- **NIH application ID:** 10168670
- **Project number:** 5R01NS110630-03
- **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:** $415,135
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168670

## Citation

> US National Institutes of Health, RePORTER application 10168670, Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis (5R01NS110630-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168670. Licensed CC0.

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