Developmental plasticity of CNS microglia

Abstract

Microglia arise from CD45 ؉ bone marrow precursors that colonize the fetal brain and play a key role in central nervous system inflammatory conditions. We report that parenchymal microglia are uncommitted myeloid progenitors of immature dendritic cells and macrophages by several criteria, including surface expression of ''empty'' class II MHC protein and their cysteine protease (cathepsin) profile. Microglia express receptors for stem cell factor and can be skewed toward more dendritic cell or macrophage-like profiles in response to the lineage growth factors granulocyte͞ macrophage colony-stimulating factor or macrophage colonystimulating factor. Thus, in contrast to other organs, where terminally differentiated populations of resident dendritic cells and͞ or macrophages outnumber colonizing precursors, the majority of microglia within the brain remain in an undifferentiated state. P arenchymal microglia are ubiquitously distributed in the central nervous system (CNS) where they comprise up to 20% of the total non-neuronal cell population (1). These cells are thought to play a prominent role in infectious, traumatic, inflammatory, ischemic, and degenerative CNS disease processes. The role of microglia as mediators of CNS inflammation is, in part, promulgated through their ability to process and present class II-restricted antigens to CD4 ϩ T cells (2, 3).Microglial cells are derived from CD45 ϩ bone marrow precursors of the myeloid lineage, which also can give rise to macrophages, dendritic cells (DC), and granulocytes. Studies by using irradiation chimeras show that the adult brain has two subsets of microglia (3): the resting microglia, which are ramified throughout the brain parenchyma and are mostly a permanent population, and the perivascular microglia, which are periodically replaced by bone marrow-derived elements and are strategically located in the basal lamina of brain capillaries and the choroid plexus. The only known difference between these microglial populations is CD45 expression, which is high on perivascular and low on parenchymal microglia (4). In general, CD45 high cells also express more class II MHC and costimulatory molecules. However, it is still unclear whether the parenchymal and perivascular microglia represent the same cellular population at a different activation state, owing to microenvironmental influences, or whether these populations are more distinct.Traditionally, parenchymal microglia have been considered to be resident macrophages of the brain. However, several pieces of evidence suggest a more complex picture. For example, op͞op mice, which are deficient in macrophage colony-stimulating factor (M-CSF) and consequently are depleted of tissue-resident macrophages in several areas, do not exhibit a large reduction in the overall brain microglial population (5-7). Also, previous studies show generation of ''DC-like'' antigen-presenting cells (APC) from mixed glial cultures (8). Cells clearly displaying macrophage-and DC-like characteristics have been identified from the CNS of m...

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

“…51,52 Moreover, neurogenesis can be boosted by injections of minocycline, a compound that blocks the activation of microglia. 53 Interestingly, resident parenchymal microglia do not seem to be fully differentiated into typical myeloid cells 50 and as mentioned, are poor APCs. 49,50 On the other hand, newly differentiated donor-derived microglia seem to be fully committed myeloid cells and may thus be more easily activated by environmental cues.…”

“…53 Interestingly, resident parenchymal microglia do not seem to be fully differentiated into typical myeloid cells 50 and as mentioned, are poor APCs. 49,50 On the other hand, newly differentiated donor-derived microglia seem to be fully committed myeloid cells and may thus be more easily activated by environmental cues. Consequently, blood-derived microglia may produce higher levels of proinflammatory cytokines, which could lead to decreased neurogenesis in the brain.…”

“…It is known that tissue macrophages express high levels of MHC-II, and are thus good APCs, whereas parenchymal microglia express low levels of this protein, indicating that they are poor APCs. 49,50 However, it has been shown recently that microglia originating from BMDCs express higher levels of MHC-II than their residential counterparts, 36,43 which suggests that these infiltrated microglia are good APCs and may thus be able to activate cells of the adaptive immune system. Therefore, microglia of blood origin may contribute to the development of debilitating immune processes in the cerebral environment.…”

Behavior of in vitro cultured ameboid microglial cells migrating on Müller cell end‐feet in the quail embryo retina

“…To date, most methods of microglial cell culture have obtained primary mixed cell cultures after tissue dissociation, generally from neonatal rodent brain or retina (Dobrenis, 1998;Giulian and Baker, 1986;Roque and Caldwell, 1993;Santambrogio et al, 2001;Wang et al, 2005). These primary mixed cell cultures are maintained for 7-14 days and microglia are then isolated by shaking because of their weak adherence to the cell substrate.…”

Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences

“…59 Cells displaying immunoreactivity towards markers of dendritic cells have been observed in several experimental brain inflammatory conditions. 12,[50][51][52][53][54][55][56][57][58] In addition, the phenomenon of epitope spreading 59,60 also suggests that, once brain inflammation occurs, new antigens being released from the brain during inflammatory processes can stimulate additional immune responses. However, evidence against antigens released from the brain causing autoimmune diseases is strong, and includes the lack of autoimmunity following stroke, brain surgery, brain tumors, and brain infarcts.…”