Resident microglia and hematogenous macrophages as phagocytes in adoptively transferred experimental autoimmune transferred experimental autoimmune encephalomyelitis: An investigation using rat radiation bone marrow chimeras

Abstract

Hematogenous macrophages are known to be involved in the induction of tissue damage in the central nervous system (CNS) as well as of clinical symptoms in experimental autoimmune encephalomyelitis (EAE). Although resident microglia can become phagocytic under certain circumstances, little is known about the role of these cells in brain inflammation in vivo. We thus studied EAE in the model of radiation bone marrow chimeras that allows us to distinguish donor-derived hematogenous cells from resident effector cells. Inflammation in the CNS was qualitatively and quantitatively similar in chimeras compared to fully histocompatible Lewis rats. Although activated resident microglial cells were outnumbered four- to sevenfold in EAE lesions by hematogenous macrophages, the number of resident microglia with ingested myelin was equal to that of macrophages containing myelin debris. Phagocytic resident microglia, expressing the macrophage activation marker ED1, showed ramified as well as amoeboid morphology. From our studies the following conclusions can be drawn. First, a considerable proportion of resident microglia upregulated ED1. Second, resident microglia provide a small but substantial source of brain macrophages in EAE as compared to the large influx of macrophages. Third, our results suggest that microglia, due to their strategic position within the CNS, are more effective in removal of myelin debris compared to hematogenous macrophages.

Kinetics and Cellular Origin of Cytokines in the Central Nervous System: Insight into Mechanisms of Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

“…At the peak of disease, CD45 high macrophages outnumber microglia. This has also been demonstrated to occur in rat MBP-induced EAE using bone marrow chimeras, where hematogenous donor macrophages outnumbered resident host-derived microglia in the spinal cord 4-to 7-fold (37). The early expression of the chemokines MCP-1, RANTES, and IP-10 in the CNS provides a mechanism for the later influx of macrophages and T cells.…”

TGF-β signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis

“…To address this issue we developed bone marrow (BM) chimeras in which transgene expression was restricted either to DCs or microglial cells. The model of radiation-BM chimeras is commonly used to selectively manipulate the genotype of the peripheral hematopoietic immune system from that of the CNS resident cells, given that microglial cells are radioresistant and are not repopulated after BM reconstitution (23,24). To distinguish between donor-derived cells versus host cells, we used congenic donor and recipient mice.…”

Persistent Macrophage/Microglial Activation and Myelin Disruption after Experimental Autoimmune Encephalomyelitis in Tissue Inhibitor of Metalloproteinase-1-Deficient Mice

“…24 In this context, macrophages, as well as resident microglia, have been shown to be important mediators of myelin injury through direct cellular injury (phagocytosis) [25][26][27] and through promoting autoreactive T-cell responses by functioning as antigen presenting cells. 28 -30 To address the possibility that enhanced microgliosis/ macrophage activity contributed to the EAE-related pathology in TIMP-1 Ϫ/Ϫ mice, we examined whether the spinal cords from MOG -immunized WT and TIMP-1 Ϫ/Ϫ mice exhibited any differences in the infiltration of peripheral macrophages and/or activation of microglia.…”