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Pathologic and Protective Roles for Microglial Subsets and Bone Marrow- and Blood-Derived Myeloid Cells in Central Nervous System Inflammation.

Wlodarczyk A, Cédile O, Jensen KN, Jasson A, Mony JT, Khorooshi R, Owens T - Front Immunol (2015)

Bottom Line: However, as in other tissues, neuroinflammation can have beneficial as well as pathological outcomes.Moreover, in contrast to BMDM/DC, both subsets of microglia express protective interferon-beta (IFNβ), high levels of colony-stimulating factor-1 receptor, and do not express the Th1-associated transcription factor T-bet.Taken together, our data suggest that CD11c(+) microglia, CD11c(-) microglia, and infiltrating BMDM/DC represent separate and distinct populations and illustrate the heterogeneity of the CNS inflammatory environment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark , Odense , Denmark.

ABSTRACT
Inflammation is a series of processes designed for eventual clearance of pathogens and repair of damaged tissue. In the context of autoimmune recognition, inflammatory processes are usually considered to be pathological. This is also true for inflammatory responses in the central nervous system (CNS). However, as in other tissues, neuroinflammation can have beneficial as well as pathological outcomes. The complex role of encephalitogenic T cells in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) may derive from heterogeneity of the myeloid cells with which these T cells interact within the CNS. Myeloid cells, including resident microglia and infiltrating bone marrow-derived cells, such as dendritic cells (DC) and monocytes/macrophages [bone marrow-derived macrophages (BMDM)], are highly heterogeneous populations that may be involved in neurotoxicity and also immunoregulation and regenerative processes. Better understanding and characterization of myeloid cell heterogeneity is essential for future development of treatments controlling inflammation and inducing neuroprotection and neuroregeneration in diseased CNS. Here, we describe and compare three populations of myeloid cells: CD11c(+) microglia, CD11c(-) microglia, and CD11c(+) blood-derived cells in terms of their pathological versus protective functions in the CNS of mice with EAE. Our data show that CNS-resident microglia include functionally distinct subsets that can be distinguished by their expression of CD11c. These subsets differ in their expression of Arg-1, YM1, iNOS, IL-10, and IGF-1. Moreover, in contrast to BMDM/DC, both subsets of microglia express protective interferon-beta (IFNβ), high levels of colony-stimulating factor-1 receptor, and do not express the Th1-associated transcription factor T-bet. Taken together, our data suggest that CD11c(+) microglia, CD11c(-) microglia, and infiltrating BMDM/DC represent separate and distinct populations and illustrate the heterogeneity of the CNS inflammatory environment.

No MeSH data available.


Related in: MedlinePlus

CD11c+ microglia emerge in response to neuroinflammation. (A) Flow cytometry analysis shows a significant increase of CD11c+ microglia, presented as a percentage of total microglia, in EAE, NMO-like disease, and cuprizone-induced demyelination. Data are presented as means ± SEM of three individual experiments (n ≥ 6), **P < 0.01 ***P < 0.005, ****P < 0.001. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE from three individual experiments. Arrowheads point to CD11c (red) single positive cells, asterisks point to Iba1 (green) single positive cells, and arrows point to cells co-expressing CD11c marker with Iba1.
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Figure 2: CD11c+ microglia emerge in response to neuroinflammation. (A) Flow cytometry analysis shows a significant increase of CD11c+ microglia, presented as a percentage of total microglia, in EAE, NMO-like disease, and cuprizone-induced demyelination. Data are presented as means ± SEM of three individual experiments (n ≥ 6), **P < 0.01 ***P < 0.005, ****P < 0.001. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE from three individual experiments. Arrowheads point to CD11c (red) single positive cells, asterisks point to Iba1 (green) single positive cells, and arrows point to cells co-expressing CD11c marker with Iba1.

Mentions: CD11b and CD11c form integrin heterodimers with CD18 and function as complement receptors. Both can be expressed by microglia [reviewed in Ref. (10)]. However, CD11c expression is usually attributed to activation of these cells. In humans, CD11c was shown to be constitutively expressed at a low level in microglia and upregulated in Alzheimer’s disease (AD) (26). CD11c+ Iba1+ cells were found in developing mouse brain as early as E16, they were also evident during postnatal neurodevelopment P2 (27), while in adult brain they were hardly visible (20, 27). We have confirmed prominence of CD11c-positive cells in the developing brain, most of them being CCR2− CX3CR1+ Iba1+ microglia (unpublished data). In adult mice, only very few CD11c+ cells are present in the steady state, averaging 2–3% of total microglia (Figure 2A). However, their proportions increase dramatically during active neuroinflammation, such as in EAE (19), cuprizone-induced demyelination (23), and in a mouse model for neuromyelitis optica (Figure 2A), and also in an animal model for AD (28). Due to many phenotypic overlaps, bone marrow-derived macrophages (BMDM)/DC and microglia within the inflamed CNS are difficult to distinguish from each other by histology. Nevertheless, we assessed the localization of CD11c+ cells within the inflamed spinal cord. We identified three different populations of myeloid cells within the lesion: Iba1+ CD11c+ and Iba1+CD11c− cells, that are likely to include microglia/BMDM, as well as CD11c+ Iba1− cells, most likely DC. Beside differential expression of these markers, they show different morphology, ranging from round, as well as dendritic-like CD11c+ Iba1− cells to amoeboid double-positive and Iba1-single positive cells. All of them were uniformly distributed within the lesion, with obvious possibility for interaction with T cells and with each other (Figure 2B). These data emphasize the high morphological and phenotypic heterogeneity of myeloid cell populations in neuroinflammation.


Pathologic and Protective Roles for Microglial Subsets and Bone Marrow- and Blood-Derived Myeloid Cells in Central Nervous System Inflammation.

Wlodarczyk A, Cédile O, Jensen KN, Jasson A, Mony JT, Khorooshi R, Owens T - Front Immunol (2015)

CD11c+ microglia emerge in response to neuroinflammation. (A) Flow cytometry analysis shows a significant increase of CD11c+ microglia, presented as a percentage of total microglia, in EAE, NMO-like disease, and cuprizone-induced demyelination. Data are presented as means ± SEM of three individual experiments (n ≥ 6), **P < 0.01 ***P < 0.005, ****P < 0.001. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE from three individual experiments. Arrowheads point to CD11c (red) single positive cells, asterisks point to Iba1 (green) single positive cells, and arrows point to cells co-expressing CD11c marker with Iba1.
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Figure 2: CD11c+ microglia emerge in response to neuroinflammation. (A) Flow cytometry analysis shows a significant increase of CD11c+ microglia, presented as a percentage of total microglia, in EAE, NMO-like disease, and cuprizone-induced demyelination. Data are presented as means ± SEM of three individual experiments (n ≥ 6), **P < 0.01 ***P < 0.005, ****P < 0.001. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE from three individual experiments. Arrowheads point to CD11c (red) single positive cells, asterisks point to Iba1 (green) single positive cells, and arrows point to cells co-expressing CD11c marker with Iba1.
Mentions: CD11b and CD11c form integrin heterodimers with CD18 and function as complement receptors. Both can be expressed by microglia [reviewed in Ref. (10)]. However, CD11c expression is usually attributed to activation of these cells. In humans, CD11c was shown to be constitutively expressed at a low level in microglia and upregulated in Alzheimer’s disease (AD) (26). CD11c+ Iba1+ cells were found in developing mouse brain as early as E16, they were also evident during postnatal neurodevelopment P2 (27), while in adult brain they were hardly visible (20, 27). We have confirmed prominence of CD11c-positive cells in the developing brain, most of them being CCR2− CX3CR1+ Iba1+ microglia (unpublished data). In adult mice, only very few CD11c+ cells are present in the steady state, averaging 2–3% of total microglia (Figure 2A). However, their proportions increase dramatically during active neuroinflammation, such as in EAE (19), cuprizone-induced demyelination (23), and in a mouse model for neuromyelitis optica (Figure 2A), and also in an animal model for AD (28). Due to many phenotypic overlaps, bone marrow-derived macrophages (BMDM)/DC and microglia within the inflamed CNS are difficult to distinguish from each other by histology. Nevertheless, we assessed the localization of CD11c+ cells within the inflamed spinal cord. We identified three different populations of myeloid cells within the lesion: Iba1+ CD11c+ and Iba1+CD11c− cells, that are likely to include microglia/BMDM, as well as CD11c+ Iba1− cells, most likely DC. Beside differential expression of these markers, they show different morphology, ranging from round, as well as dendritic-like CD11c+ Iba1− cells to amoeboid double-positive and Iba1-single positive cells. All of them were uniformly distributed within the lesion, with obvious possibility for interaction with T cells and with each other (Figure 2B). These data emphasize the high morphological and phenotypic heterogeneity of myeloid cell populations in neuroinflammation.

Bottom Line: However, as in other tissues, neuroinflammation can have beneficial as well as pathological outcomes.Moreover, in contrast to BMDM/DC, both subsets of microglia express protective interferon-beta (IFNβ), high levels of colony-stimulating factor-1 receptor, and do not express the Th1-associated transcription factor T-bet.Taken together, our data suggest that CD11c(+) microglia, CD11c(-) microglia, and infiltrating BMDM/DC represent separate and distinct populations and illustrate the heterogeneity of the CNS inflammatory environment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark , Odense , Denmark.

ABSTRACT
Inflammation is a series of processes designed for eventual clearance of pathogens and repair of damaged tissue. In the context of autoimmune recognition, inflammatory processes are usually considered to be pathological. This is also true for inflammatory responses in the central nervous system (CNS). However, as in other tissues, neuroinflammation can have beneficial as well as pathological outcomes. The complex role of encephalitogenic T cells in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) may derive from heterogeneity of the myeloid cells with which these T cells interact within the CNS. Myeloid cells, including resident microglia and infiltrating bone marrow-derived cells, such as dendritic cells (DC) and monocytes/macrophages [bone marrow-derived macrophages (BMDM)], are highly heterogeneous populations that may be involved in neurotoxicity and also immunoregulation and regenerative processes. Better understanding and characterization of myeloid cell heterogeneity is essential for future development of treatments controlling inflammation and inducing neuroprotection and neuroregeneration in diseased CNS. Here, we describe and compare three populations of myeloid cells: CD11c(+) microglia, CD11c(-) microglia, and CD11c(+) blood-derived cells in terms of their pathological versus protective functions in the CNS of mice with EAE. Our data show that CNS-resident microglia include functionally distinct subsets that can be distinguished by their expression of CD11c. These subsets differ in their expression of Arg-1, YM1, iNOS, IL-10, and IGF-1. Moreover, in contrast to BMDM/DC, both subsets of microglia express protective interferon-beta (IFNβ), high levels of colony-stimulating factor-1 receptor, and do not express the Th1-associated transcription factor T-bet. Taken together, our data suggest that CD11c(+) microglia, CD11c(-) microglia, and infiltrating BMDM/DC represent separate and distinct populations and illustrate the heterogeneity of the CNS inflammatory environment.

No MeSH data available.


Related in: MedlinePlus