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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

T-bet is expressed by infiltrating BMDM/DC but not by microglia in EAE. (A) Expression of T-bet in sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system from mice with severe EAE was 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). ND, not detected. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE for four individual experiments. Arrowheads point to T-bet (red) single positive cells, asterisks point to Mac1/CD11b (green) single positive cells, and arrows point to cells co-expressing T-bet marker with Mac1/CD11b.
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Figure 8: T-bet is expressed by infiltrating BMDM/DC but not by microglia in EAE. (A) Expression of T-bet in sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system from mice with severe EAE was 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). ND, not detected. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE for four individual experiments. Arrowheads point to T-bet (red) single positive cells, asterisks point to Mac1/CD11b (green) single positive cells, and arrows point to cells co-expressing T-bet marker with Mac1/CD11b.

Mentions: We have shown that CD11c+ microglia in EAE express MHC-II and co-stimulatory molecules CD80 and CD86, and that these cells have potent ability to induce proliferation of antigen-primed CD4+ T cells (19). This has led to speculation that they may reflect a more DC-like subset of microglia, as was previously suggested, largely on the basis of morphology and CD11c expression (41). However, they differ from DC in their relative expression of Th1- and Th17-inducing cytokines and in their quantitative ability to induce such T cell responses, CD11c+ microglia being, noticeably, less effective (19). We have now further explored possible overlap between CD11c+ microglia and DC by comparison of their expression of the transcription factor T-bet. T-bet was first isolated as a novel Th1-specific T box transcription factor that controls the expression of the hallmark Th1 cytokine, IFNγ (42). T-bet is also expressed by other IFNγ-producing cells including CD8+ T cells and NK cells, and has been shown to be expressed by IgG2a+ memory B cells, where it plays a role in IFNγ-mediated class switching as well as controlling expression of the chemokine receptor CXCR3 [reviewed in Ref. (43)]. T-bet is classically associated with the Th1 CD4+ T cell subset but also controls IL23R expression by Th17 (44). It has been implicated in regulation of effector responses by CD8+ T cells (45, 46) and in control of Th-1 expression of granulocyte–macrophage colony-stimulating factor (GM-CSF or CSF2) (47), which has been proposed to be the link between pathogenic T cells and infiltrating myeloid cells (48). T-bet was reported to be required for Th1 and Th17 encephalitogenicity (49), although this has been contradicted by later studies (50). Earlier studies had shown that T-bet was also expressed by DC and regulated DC functions (45, 46), and although reported to play a role in IFNγ production by DC, that is unlikely to be a major activity of this cell type. Expression of T-bet by DC was critical for Th1 induction and for the generation of T cell memory (43). T-bet was later shown to play a role in DC control of mast cell precursor migration (51). We compared levels of T-bet mRNA in microglia and BMDM/DC isolated from the CNS of mice with EAE. Whereas CD45highCD11c+ BMDM/DC robustly expressed high levels of T-bet mRNA, it was undetectable in most microglial samples, regardless of CD11c expression (Figure 8A). The expression of T-bet is, therefore, a selective property of infiltrating cells, likely to be specific for DC based on previous reports, and does not occur in CNS-resident microglia.


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)

T-bet is expressed by infiltrating BMDM/DC but not by microglia in EAE. (A) Expression of T-bet in sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system from mice with severe EAE was 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). ND, not detected. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE for four individual experiments. Arrowheads point to T-bet (red) single positive cells, asterisks point to Mac1/CD11b (green) single positive cells, and arrows point to cells co-expressing T-bet marker with Mac1/CD11b.
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Figure 8: T-bet is expressed by infiltrating BMDM/DC but not by microglia in EAE. (A) Expression of T-bet in sorted myeloid cells (CD11c+ microglia, CD11c− microglia, and CD45highCD11c+) from the central nervous system from mice with severe EAE was 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). ND, not detected. (B) Representative confocal microscopic analysis of spinal cord from mice with severe EAE for four individual experiments. Arrowheads point to T-bet (red) single positive cells, asterisks point to Mac1/CD11b (green) single positive cells, and arrows point to cells co-expressing T-bet marker with Mac1/CD11b.
Mentions: We have shown that CD11c+ microglia in EAE express MHC-II and co-stimulatory molecules CD80 and CD86, and that these cells have potent ability to induce proliferation of antigen-primed CD4+ T cells (19). This has led to speculation that they may reflect a more DC-like subset of microglia, as was previously suggested, largely on the basis of morphology and CD11c expression (41). However, they differ from DC in their relative expression of Th1- and Th17-inducing cytokines and in their quantitative ability to induce such T cell responses, CD11c+ microglia being, noticeably, less effective (19). We have now further explored possible overlap between CD11c+ microglia and DC by comparison of their expression of the transcription factor T-bet. T-bet was first isolated as a novel Th1-specific T box transcription factor that controls the expression of the hallmark Th1 cytokine, IFNγ (42). T-bet is also expressed by other IFNγ-producing cells including CD8+ T cells and NK cells, and has been shown to be expressed by IgG2a+ memory B cells, where it plays a role in IFNγ-mediated class switching as well as controlling expression of the chemokine receptor CXCR3 [reviewed in Ref. (43)]. T-bet is classically associated with the Th1 CD4+ T cell subset but also controls IL23R expression by Th17 (44). It has been implicated in regulation of effector responses by CD8+ T cells (45, 46) and in control of Th-1 expression of granulocyte–macrophage colony-stimulating factor (GM-CSF or CSF2) (47), which has been proposed to be the link between pathogenic T cells and infiltrating myeloid cells (48). T-bet was reported to be required for Th1 and Th17 encephalitogenicity (49), although this has been contradicted by later studies (50). Earlier studies had shown that T-bet was also expressed by DC and regulated DC functions (45, 46), and although reported to play a role in IFNγ production by DC, that is unlikely to be a major activity of this cell type. Expression of T-bet by DC was critical for Th1 induction and for the generation of T cell memory (43). T-bet was later shown to play a role in DC control of mast cell precursor migration (51). We compared levels of T-bet mRNA in microglia and BMDM/DC isolated from the CNS of mice with EAE. Whereas CD45highCD11c+ BMDM/DC robustly expressed high levels of T-bet mRNA, it was undetectable in most microglial samples, regardless of CD11c expression (Figure 8A). The expression of T-bet is, therefore, a selective property of infiltrating cells, likely to be specific for DC based on previous reports, and does not occur in CNS-resident microglia.

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