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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 6

CD47 Ab Miap410 prevented recovery of mice from EAE compared with isotype control Ab MOPC-21.

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CD47 Ab Miap410 prevented recovery of mice from EAE compared with isotyp...
(A) Total number of CD45+, CD45lo (microglia), and CD45hi (blood-derived) immune cells at recovery phase (DPI 23) of EAE. (B) Total number of immune cell subtypes at recovery phase. (C–E) Representative plots of CD45lo and CD45hi within CD45+ cells (C), monocytes/macrophages/microglia within CD45+F4/80+Ly6G– cells (D), and CD11chiMHCIIhi cells within CD45lo cells (E). (F and G) Percentage (F) and total number (G) of CD11chiMHCIIhi within CD45lo cells in SCs at recovery phase. (H) Representative images of Luxol fast blue and Tmem119 staining of SCs from 3 mice of similar average clinical score. Scale bars represent 200 μm in SCs and 100 μm for zoomed images. (I) Relative surface marker expression on CD45lo cells isolated from SCs of Ab-treated mice. n = 3–4 per group. (J) Clinical score of an R-EAE mouse model given anti-CD47 Ab Miap410 or control Ab MOPC-21 every 48 hours starting at an average score of 1 (12 DPI). Data are shown as means ± SEM. n = 10 female SJL mice. *P < 0.05, **P < 0.01, ***P < 0.001. Unpaired Student’s t test was used (A, B, F, G, and I) and paired Student’s t test (J).

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