Functional dichotomy of mouse microglia developed in vitro: Differential effects of macrophage and granulocyte/macrophage colony-stimulating factor on cytokine secretion and antitoxoplasmic activity

Fischer, Hans; Bielinsky, Anja‐Katrin; Nitzgen, B.; Däubener, Walter; Hadding, U.

doi:10.1016/0165-5728(93)90180-7

Cited by 50 publications

(32 citation statements)

References 40 publications

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“…The neonatal microglial cell phenotype closely resembles that of circulating monocytes (2,(11)(12)(13), and can be skewed to a more m-like or DC-like phenotype by M-CSF or GM-CSF, respectively (13). Using global gene expression analysis, we now show that upon treatment of microglial cells with either GM-CSF or M-CSF, a large proportion of expressed genes is up-regulated or down-regulated Ͼ2.5-fold (Ͼ16%).…”

Section: Discussionmentioning

confidence: 73%

“…Morphologically, neonatal microglial cells cultured in M-CSF appear amoeboid, whereas those cultured in GM-CSF assume a dendriform shape (13). Phenotypically, neonatal microglial cells treated with M-CSF display some characteristics of macrophage (m) 3 whereas those cultured in GM-CSF assume some of the markers associated with an immature dendritic cell (DC)-like phenotype (11,13,14). Importantly, the cytokine production capacity and competence as APCs are also differentially regulated by exposure to M-CSF and GM-CSF (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

“…Thus, it appears that M-CSF plays an important role in shaping the adult resident parenchymal microglia, whereas GM-CSF could have an important role in promoting their proinflammatory function. In this respect, the functional states of microglial cells elicited by M-CSF or GM-CSF have been proposed to correspond to the resting or "activated" form of microglia, respectively (11).…”

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confidence: 99%

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Granulocyte-Macrophage Colony-Stimulating Factor Induces an Expression Program in Neonatal Microglia That Primes Them for Antigen Presentation

Belyanskaya

Riese

et al. 2002

The Journal of Immunology

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Neonatal microglial cells respond to GM-CSF and M-CSF by acquiring different morphologies and phenotypes. To investigate the extent and consequences of this process, a global gene expression analysis was performed, with significant changes in transcript levels confirmed by biochemical analyses. Primary murine microglial cells underwent substantial expression reprogramming after treatment with GM-CSF or M-CSF with many differentially expressed transcripts important in innate and adaptive immunity. In particular, many gene products involved in Ag presentation were induced by GM-CSF, but not M-CSF, thus potentially priming relatively quiescent microglia cells for Ag presentation. This function of GM-CSF is distinct from its primary function in cell proliferation and survival.

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Section: Discussionmentioning

confidence: 73%

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confidence: 99%

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confidence: 99%

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Granulocyte-Macrophage Colony-Stimulating Factor Induces an Expression Program in Neonatal Microglia That Primes Them for Antigen Presentation

Belyanskaya

Riese

et al. 2002

The Journal of Immunology

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“…Overall, murine microglia appear to respond to IFN-␥ in two ways: by inhibiting tachyzoite proliferation through both IFN-␥R and TNFR1 signaling mechanisms that stimulate NO production and by a separate pathway that is NO independent. GM-CSF, but not M-CSF, also activates murine microglia to inhibit tachyzoite replication via the generation of NO (108). Despite widespread activation, only murine astrocytes and microglia restricted to inflammatory infiltrates actually produce chemokines that actively recruit inflammatory leukocytes (339).…”

Section: Parasitesmentioning

confidence: 99%

Role of Microglia in Central Nervous System Infections

et al. 2004

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The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed

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“…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)(6)(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 mice with experimental allergic encephalitis and toxoplasmic encephalitis (9).…”

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Developmental plasticity of CNS microglia

Santambrogio

Belyanskaya

Fischer

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

286

234

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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...

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Functional dichotomy of mouse microglia developed in vitro: Differential effects of macrophage and granulocyte/macrophage colony-stimulating factor on cytokine secretion and antitoxoplasmic activity

Cited by 50 publications

References 40 publications

Granulocyte-Macrophage Colony-Stimulating Factor Induces an Expression Program in Neonatal Microglia That Primes Them for Antigen Presentation

Granulocyte-Macrophage Colony-Stimulating Factor Induces an Expression Program in Neonatal Microglia That Primes Them for Antigen Presentation

Role of Microglia in Central Nervous System Infections

Developmental plasticity of CNS microglia

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