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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 3

CD47 Ab Miap410 reduces immune cell infiltration into SCs and delayed EAE onset but worsens paresis.

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CD47 Ab Miap410 reduces immune cell infiltration into SCs and delayed EA...
(A) Clinical scores. Ab treatments started on DPI 0. Data are shown as the means ± SEM. n = 10 mice per group. (B) Total number of different CD45hi immune cells at peak disease (DPI 15) in Miap410 Ab– and MOPC-21 Ab–treated mice compared with nonimmunized (Ctr) mice. n = 6–8 mice per group. (C) Total number of different immune cell types. n = 6–8 mice per group. (D–I) Representative plots, and the percentage and total number of the CD4+ T cells producing IFN-γ (D–F) or producing IL-17A (G–I), at peak disease. n = 3 mice per group. (J) Representative plots of microglia, monocytes, and Mono-Macs within the CD45+F4/80+Ly6G– group of cells based on Ly6C and MHCII surface expression at peak disease compared with nonimmunized (Ctr) mice. Representative plots of CD45lo and CD45hi cells. (K) Relative protein expression on monocytes and Mono-Macs from MOPC-21 Ab–treated mice at peak disease. (L) Relative protein expressions on Mono-Macs from MOPC-21– and Miap410-treated mice at peak disease. n = 4–6 mice per group. All data were from SCs. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA with Tukey’s post hoc test was used (B and C). Paired Student’s t test (A) and unpaired Student’s t test (E, F, H, I, K, and L).

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