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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

IFNβ and IFN regulatory factors expression by microglia and infiltrating BMDM/DC in EAE. Expression of IFNβ (A), IRF7 (B), and IRF3 (C) by sorted myeloid cells (CD11c+ microglia, CD11c− microglia and CD45highCD11c+ BMDM/DC) from the CNS of mice with severe EAE as well as unmanipulated splenic CD11c+ cells was analyzed by RT-qPCR. Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) **P < 0.01.
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Figure 6: IFNβ and IFN regulatory factors expression by microglia and infiltrating BMDM/DC in EAE. Expression of IFNβ (A), IRF7 (B), and IRF3 (C) by sorted myeloid cells (CD11c+ microglia, CD11c− microglia and CD45highCD11c+ BMDM/DC) from the CNS of mice with severe EAE as well as unmanipulated splenic CD11c+ cells was analyzed by RT-qPCR. Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) **P < 0.01.

Mentions: Since neurogenesis may be considered as a part of the anti-inflammatory or protective spectrum, we asked whether these cells additionally selectively expressed other regulatory cytokines. It was recently published that IFNβ produced by a subpopulation of microglia at the peak of EAE facilitated clearance of myelin debris, thus, contributing to possible explanations for amelioration of EAE as well as MS by IFNβ (35). Moreover, we have shown that experimental induction of microglial-derived IFNβ was protective in EAE (36). We, therefore, asked whether CD11c+ microglia expressed IFNβ in EAE. Contrary to our expectations, there was no difference in expression of IFNβ mRNA by CD11c+ and CD11c− microglia isolated from the CNS of mice with EAE (Figure 6A). On this basis, there was, therefore, no evidence for a selective regulatory role for CD11c+ microglia. By contrast, infiltrating BMDM/DC expressed very low levels of IFNβ mRNA comparable to unmanipulated splenic CD11c+ cells, consistent with lack of a regulatory role for these cells, distinct from CNS-resident microglia. However, all of these brain myeloid populations may respond to type I IFN, as evidenced by equivalent expression of IRF7 and IRF3 (Figures 6B,C). Interestingly, IRF3 was upregulated in BMDM/DC compared to unmanipulated splenic CD11c+ cells (Figure 6C), suggesting ongoing active response within the CNS. These data further suggest a beneficial role for microglia in demyelinating diseases as well as emphasize functional distinctions between them and infiltrating BMDM/DC. Peripherally administered IFNβ is used as a first-line therapy for MS (37). IFNβ, constitutively expressed by microglial cells, is increased in EAE and play a protective role in the CNS (35, 36). Whether this protection might involve IFNβ-driven DC response may be speculated but would be consistent with the expression of the IFNβ response gene IRF7 by DC, which we have shown.


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)

IFNβ and IFN regulatory factors expression by microglia and infiltrating BMDM/DC in EAE. Expression of IFNβ (A), IRF7 (B), and IRF3 (C) by sorted myeloid cells (CD11c+ microglia, CD11c− microglia and CD45highCD11c+ BMDM/DC) from the CNS of mice with severe EAE as well as unmanipulated splenic CD11c+ cells was analyzed by RT-qPCR. Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) **P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: IFNβ and IFN regulatory factors expression by microglia and infiltrating BMDM/DC in EAE. Expression of IFNβ (A), IRF7 (B), and IRF3 (C) by sorted myeloid cells (CD11c+ microglia, CD11c− microglia and CD45highCD11c+ BMDM/DC) from the CNS of mice with severe EAE as well as unmanipulated splenic CD11c+ cells was analyzed by RT-qPCR. Data are presented as means ± SEM of three individual experiments (n ≥ 5, where n represents a pool of 2–3 individual mice) **P < 0.01.
Mentions: Since neurogenesis may be considered as a part of the anti-inflammatory or protective spectrum, we asked whether these cells additionally selectively expressed other regulatory cytokines. It was recently published that IFNβ produced by a subpopulation of microglia at the peak of EAE facilitated clearance of myelin debris, thus, contributing to possible explanations for amelioration of EAE as well as MS by IFNβ (35). Moreover, we have shown that experimental induction of microglial-derived IFNβ was protective in EAE (36). We, therefore, asked whether CD11c+ microglia expressed IFNβ in EAE. Contrary to our expectations, there was no difference in expression of IFNβ mRNA by CD11c+ and CD11c− microglia isolated from the CNS of mice with EAE (Figure 6A). On this basis, there was, therefore, no evidence for a selective regulatory role for CD11c+ microglia. By contrast, infiltrating BMDM/DC expressed very low levels of IFNβ mRNA comparable to unmanipulated splenic CD11c+ cells, consistent with lack of a regulatory role for these cells, distinct from CNS-resident microglia. However, all of these brain myeloid populations may respond to type I IFN, as evidenced by equivalent expression of IRF7 and IRF3 (Figures 6B,C). Interestingly, IRF3 was upregulated in BMDM/DC compared to unmanipulated splenic CD11c+ cells (Figure 6C), suggesting ongoing active response within the CNS. These data further suggest a beneficial role for microglia in demyelinating diseases as well as emphasize functional distinctions between them and infiltrating BMDM/DC. Peripherally administered IFNβ is used as a first-line therapy for MS (37). IFNβ, constitutively expressed by microglial cells, is increased in EAE and play a protective role in the CNS (35, 36). Whether this protection might involve IFNβ-driven DC response may be speculated but would be consistent with the expression of the IFNβ response gene IRF7 by DC, which we have shown.

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