Myelin ingestion alters macrophage antigen-presenting function in vitro and in vivo

Abstract

During MS, phagocytosing myelin-containing macrophages arise and lie in close proximity to T cells. To date, it has not been addressed whether these myelin-laden macrophages have the capacity to present antigens to T cells and whether this contributes to inflammation in disease. We demonstrate that in vitro-generated human and mouse myelin-laden macrophages expressed MHC class I and II and costimulatory molecules and are thus well equipped for antigen presentation. Human myelin-laden macrophages exhibited normal endocytosis of particulate and soluble antigens. In addition, human myelin-laden macrophages elicited active T cell proliferation of naïve as well as memory T cells. Furthermore, mouse myelin-laden macrophages induced primary antigen-specific CD4(+) T cell proliferation in vivo but transiently diminished IFN-γ release. Functionally, MOG peptide-loaded myelin-laden mouse macrophages modestly but significantly reduced the severity of MOG peptide-induced EAE. These data show that myelin uptake results in the induction of a population of macrophages that retains antigen-presenting capacity and limits autoimmune-mediated disease.

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

“…Previous studies have referred to myelin-containing myeloid cells as foamy macrophages. Ingestion of myelin by MDMs in vitro induces an anti-inflammatory cytokine response, a phenotype also observed in human MS lesions (4,5). Previously, we and others have observed that human adult brain-derived microglia in vitro display an increased ability to phagocytose myelin as compared with MDMs (6,7).…”

Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis

“…These leukocytes enter the white matter by crossing the blood-brain barrier (BBB) in areas of inflammation called the perivascular cuffs (1)(2)(3), as well as through the CNS-meningeal barrier (4,5). The accumulation and activation of leukocytes in areas of infiltration initiates a cascade of events leading to the loss of BBB integrity, which further aids the transmigration of leukocytes into the brain parenchyma (3,6,7). Recent studies highlight the existence of a metabolic switch within leukocytes that intricately regulates their activation states by changing their metabolic profiles.…”

Crosstalk with Inflammatory Macrophages Shapes the Regulatory Properties of Multipotent Adult Progenitor Cells

“…Macrophages have a bimodal action in autoimmune-mediated CNS diseases; while demyelinating incidents of the CNS drive macrophages and microglia activation thus contributing to the disease pathogenesis [6, 64, 65], macrophage clearance of myelin debris facilitates remyelination and reshapes their morphology towards acquisition of an anti-inflammatory and neuroprotective phenotype [30, 66–68]. Therefore, it is of high importance to elucidate how MAPC modulate the features of myeloid cell types since intravenously transplanted cells are likely to be localized in close proximity with myeloid cells in the CNS and periphery [37, 61, 69].…”