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

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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 progressive MS, the information obtained from this project can help us develop next-generation anti-CD20-based drugs to treat this intractable form of the disease.