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CD47 antibody blockade suppresses microglia-dependent phagocytosis and monocyte transition to macrophages, impairing recovery in EAE
Huan Wang, … , Sridaran Natesan, Francis W. Luscinskas
Huan Wang, … , Sridaran Natesan, Francis W. Luscinskas
Published September 30, 2021
Citation Information: JCI Insight. 2021;6(21):e148719. https://doi.org/10.1172/jci.insight.148719.
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Research Article Inflammation

CD47 antibody blockade suppresses microglia-dependent phagocytosis and monocyte transition to macrophages, impairing recovery in EAE

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Abstract

Experimental autoimmune encephalomyelitis (EAE) is a well-characterized animal model of multiple sclerosis. During the early phase of EAE, infiltrating monocytes and monocyte-derived macrophages contribute to T cell recruitment, especially CD4+ T cells, into the CNS, resulting in neuronal demyelination; however, in later stages, they promote remyelination and recovery by removal of myelin debris by phagocytosis. Signal regulatory protein α and CD47 are abundantly expressed in the CNS, and deletion of either molecule is protective in myelin oligodendrocyte glycoprotein–induced EAE because of failed effector T cell expansion and trafficking. Here we report that treatment with the function blocking CD47 Ab Miap410 substantially reduced the infiltration of pathogenic immune cells but impaired recovery from paresis. The underlying mechanism was by blocking the emergence of CD11chiMHCIIhi microglia at peak disease that expressed receptors for phagocytosis, scavenging, and lipid catabolism, which mediated clearance of myelin debris and the transition of monocytes to macrophages in the CNS. In the recovery phase of EAE, Miap410 Ab–treated mice had worsening paresis with sustained inflammation and limited remyelination as compared with control Ab–treated mice. In summary, Ab blockade of CD47 impaired resolution of CNS inflammation, thus worsening EAE.

Authors

Huan Wang, Gail Newton, Liguo Wu, Lih-Ling Lin, Amy S. Miracco, Sridaran Natesan, Francis W. Luscinskas

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Figure 8

Diagram for effects of CD47 Ab Miap410 on EAE mouse model.

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Diagram for effects of CD47 Ab Miap410 on EAE mouse model.
1. MOG immuni...
1. MOG immunization triggers an immune response to myelin that induces migration of T effector cells and myeloid cells into the CNS. 2. Infiltrated immune cells release proinflammatory chemokines and cytokines that promote inflammation and neuronal demyelination in the white matter of CNS, resulting in limb paresis. 3. Cytokines released by inflammatory cells activate resident microglia to express high amounts of CD11; MHCII; multiple phagocytic receptors, CD64 (FcγR1), CD36/scavenger receptor, TREM2, and Clec7A; and the autography protein LC3B-II. Infiltrated monocytes transition to macrophages and express increased amounts of F4/80 and CD64 (FcγR1). 4. Activated microglia and M2-like macrophages phagocytose the myelin fragments, damaged cells, and tissue debris, promoting resolution of the inflammation. 5. Inflammation resolves, remyelination occurs, and mice show recovery from paresis. 6. CD47 Ab Miap410 inhibits microglia activation and monocyte transition into macrophages and results in sustained SC inflammation and worsening limb paresis.

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ISSN 2379-3708

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