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.
Highlights
Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS with characteristic histopathologic lesions that cause significant morbidity and mortality worldwide [1]
myelin oligodendrocyte glycoprotein (MOG) immunization induces paresis, immune cell infiltration and demyelination of the spinal cords (SCs) in C57BL/6 mice We developed multicolor flow cytometry panels to phenotype lymphocytic and myeloid immune cells isolated from spinal cords (SCs) of C57BL/6J mice immunized with MOG and sacrificed at peak of disease and at recovery phase, and from non-immunized age-matched female mice for comparison purposes based on the flow cytometric data reported by Caravagna and colleagues [27] (Supplemental Figure 1)
SCs harvested from mice at peak paresis scores contained a large number of immune cells that separated into two distinct populations based on CD45 leukocyte antigen staining: a large population of blood derived CD45high leukocytes and a smaller population of resident microglia CD45low immune cells (Figure 1B, C)
Summary
Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS with characteristic histopathologic lesions that cause significant morbidity and mortality worldwide [1]. Experimental autoimmune encephalomyelitis (EAE) is a preclinical animal model that approximates key pathological features of MS including inflammation, demyelination, reactive microgliosis and astrocytic gliosis, and axonal loss [1,2,3,4]. In the CNS, extravasated immune cells and activation of resident CNS cells, including the microglia, oligodendroglia, and astrocytes, collectively have been shown to contribute to nerve demyelination, and neuron injury, damage and loss (reviewed in [5]). SIRPα is expressed in myeloid leukocytes, glial cells, and neurons within the CNS and at low amounts in vascular endothelial cells (1015). Binding of CD47 on circulating blood cells to SIRPα expressed on splenic myeloid cells transmits a negative “don’t eat me” inhibitory signal, preventing hematopoietic cell phagocytosis [16]
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