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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.


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Proliferation of microglial and BMDM/DC populations during EAE. Representative flow cytometry profiles of six individual central nervous system suspensions prepared from mice with severe EAE showing BrdU incorporation by CD11c− microglia (green) and CD11c+ microglia (red) based on negative control (blue) (A). Flow cytometry analysis shows a significant increase in percentage of proliferating (incorporating BrdU) microglia during EAE compared to naive controls (B). Expression of CSF1R in fluorescence-activated cell sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system was analyzed by quantitative real-time PCR (C). Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) *P < 0.05.
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Figure 7: Proliferation of microglial and BMDM/DC populations during EAE. Representative flow cytometry profiles of six individual central nervous system suspensions prepared from mice with severe EAE showing BrdU incorporation by CD11c− microglia (green) and CD11c+ microglia (red) based on negative control (blue) (A). Flow cytometry analysis shows a significant increase in percentage of proliferating (incorporating BrdU) microglia during EAE compared to naive controls (B). Expression of CSF1R in fluorescence-activated cell sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system was analyzed by quantitative real-time PCR (C). Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) *P < 0.05.

Mentions: Microglia have been shown to be a self-renewing population within the CNS. Their proliferation in response to neurodegeneration and their maintenance in adult mice were reported to be dependent on macrophage colony-stimulating factor receptor (CSF1R) signaling (25, 40). CSF1R signaling in response to its ligands, CSF1 and IL-34, induces microglial proliferation (40), suggesting tonic self-renewal as a component of normal homeostasis. Given the emergence of CD11c+ microglia in neuroinflammation, we asked whether CSF1R signaling might play a selective role in expansion of these cells. We used BrdU incorporation to assess microglial proliferation. Both CD11c+ and CD11c− populations of microglia proliferated equivalently during EAE (Figures 7A,B), arguing against proliferation per se as basis for relative expansion of CD11c+ cells. Consistent with this, there was no significant difference in expression of CSF1R by CD11c+ and CD11c− microglia (Figure 7C). Strikingly, infiltrating BMDM/DC (CD45highCD11c+ cells) expressed very low levels of CSF1R (Figure 7C). This again emphasizes that differences between subsets of CNS-resident microglia are minor when both are compared to BMDM/DC.


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)

Proliferation of microglial and BMDM/DC populations during EAE. Representative flow cytometry profiles of six individual central nervous system suspensions prepared from mice with severe EAE showing BrdU incorporation by CD11c− microglia (green) and CD11c+ microglia (red) based on negative control (blue) (A). Flow cytometry analysis shows a significant increase in percentage of proliferating (incorporating BrdU) microglia during EAE compared to naive controls (B). Expression of CSF1R in fluorescence-activated cell sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system was analyzed by quantitative real-time PCR (C). Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) *P < 0.05.
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Related In: Results  -  Collection

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Show All Figures
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Figure 7: Proliferation of microglial and BMDM/DC populations during EAE. Representative flow cytometry profiles of six individual central nervous system suspensions prepared from mice with severe EAE showing BrdU incorporation by CD11c− microglia (green) and CD11c+ microglia (red) based on negative control (blue) (A). Flow cytometry analysis shows a significant increase in percentage of proliferating (incorporating BrdU) microglia during EAE compared to naive controls (B). Expression of CSF1R in fluorescence-activated cell sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system was analyzed by quantitative real-time PCR (C). Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) *P < 0.05.
Mentions: Microglia have been shown to be a self-renewing population within the CNS. Their proliferation in response to neurodegeneration and their maintenance in adult mice were reported to be dependent on macrophage colony-stimulating factor receptor (CSF1R) signaling (25, 40). CSF1R signaling in response to its ligands, CSF1 and IL-34, induces microglial proliferation (40), suggesting tonic self-renewal as a component of normal homeostasis. Given the emergence of CD11c+ microglia in neuroinflammation, we asked whether CSF1R signaling might play a selective role in expansion of these cells. We used BrdU incorporation to assess microglial proliferation. Both CD11c+ and CD11c− populations of microglia proliferated equivalently during EAE (Figures 7A,B), arguing against proliferation per se as basis for relative expansion of CD11c+ cells. Consistent with this, there was no significant difference in expression of CSF1R by CD11c+ and CD11c− microglia (Figure 7C). Strikingly, infiltrating BMDM/DC (CD45highCD11c+ cells) expressed very low levels of CSF1R (Figure 7C). This again emphasizes that differences between subsets of CNS-resident microglia are minor when both are compared to BMDM/DC.

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