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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

Function-related gene expression by CD11c− and CD11c+ microglia in CX3CR1gfp/gfp and B6 mice in EAE. Expression of IL-10, ARG1, YM1, iNOS, and IGF-1 in fluorescence-activated cell sorted CD11c+ microglia and CD11c− microglia from the central nervous system from mice with severe EAE were analyzed by quantitative real-time PCR. 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; **P < 0.01.
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Figure 4: Function-related gene expression by CD11c− and CD11c+ microglia in CX3CR1gfp/gfp and B6 mice in EAE. Expression of IL-10, ARG1, YM1, iNOS, and IGF-1 in fluorescence-activated cell sorted CD11c+ microglia and CD11c− microglia from the central nervous system from mice with severe EAE were analyzed by quantitative real-time PCR. 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; **P < 0.01.

Mentions: Microglial phenotypic heterogeneity may also reflect functional status (1, 32), as has been described for macrophages [reviewed in Ref. (33)]. Classically activated macrophages secrete inflammatory cytokines and mediators involved in host defense, such as tumor necrosis factor (TNFα), IL-12, or nitric oxide (NO) produced by inducible NO synthase (iNOS). By contrast, alternatively activated macrophages that are involved in the regulation of the immune response to limit inflammation and promote tissue repair express arginase-1 (ARG1) or chitinase-like proteins, such as YM1. Such cells also secrete growth factors, such as insulin-like growth factor 1 (IGF-1) or anti-inflammatory cytokine IL-10 (33). We have addressed functional correlates to CD11c phenotypic distinction for microglia sorted from the CNS of B6 and CX3CR1GFP/GFP mice with EAE, by analysis of mRNA levels of ARG1, YM1, iNOS, IL-10, and IGF1. All of them showed clear-cut preferential expression by one or another microglial subset (Figure 4). There was no difference in TNFα expression between these microglial populations (not shown). These results, therefore, point to functional distinctions between CD11c+ and CD11c− microglia. Moreover, CX3CR1 deficiency did not influence M1/M2-associated gene expression in microglia except for YM1, which was upregulated in CX3CR1-deficient microglia (Figure 4). These data suggest that the susceptibility to EAE in CX3CR1-deficient mice is not dependent on microglial M1/M2 phenotype.


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)

Function-related gene expression by CD11c− and CD11c+ microglia in CX3CR1gfp/gfp and B6 mice in EAE. Expression of IL-10, ARG1, YM1, iNOS, and IGF-1 in fluorescence-activated cell sorted CD11c+ microglia and CD11c− microglia from the central nervous system from mice with severe EAE were analyzed by quantitative real-time PCR. 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; **P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4562247&req=5

Figure 4: Function-related gene expression by CD11c− and CD11c+ microglia in CX3CR1gfp/gfp and B6 mice in EAE. Expression of IL-10, ARG1, YM1, iNOS, and IGF-1 in fluorescence-activated cell sorted CD11c+ microglia and CD11c− microglia from the central nervous system from mice with severe EAE were analyzed by quantitative real-time PCR. 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; **P < 0.01.
Mentions: Microglial phenotypic heterogeneity may also reflect functional status (1, 32), as has been described for macrophages [reviewed in Ref. (33)]. Classically activated macrophages secrete inflammatory cytokines and mediators involved in host defense, such as tumor necrosis factor (TNFα), IL-12, or nitric oxide (NO) produced by inducible NO synthase (iNOS). By contrast, alternatively activated macrophages that are involved in the regulation of the immune response to limit inflammation and promote tissue repair express arginase-1 (ARG1) or chitinase-like proteins, such as YM1. Such cells also secrete growth factors, such as insulin-like growth factor 1 (IGF-1) or anti-inflammatory cytokine IL-10 (33). We have addressed functional correlates to CD11c phenotypic distinction for microglia sorted from the CNS of B6 and CX3CR1GFP/GFP mice with EAE, by analysis of mRNA levels of ARG1, YM1, iNOS, IL-10, and IGF1. All of them showed clear-cut preferential expression by one or another microglial subset (Figure 4). There was no difference in TNFα expression between these microglial populations (not shown). These results, therefore, point to functional distinctions between CD11c+ and CD11c− microglia. Moreover, CX3CR1 deficiency did not influence M1/M2-associated gene expression in microglia except for YM1, which was upregulated in CX3CR1-deficient microglia (Figure 4). These data suggest that the susceptibility to EAE in CX3CR1-deficient mice is not dependent on microglial M1/M2 phenotype.

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