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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

CX3CR1-deficient mice are more susceptible to EAE. CX3CR1gfp/gfp and B6 mice were immunized with (MOG)p35–55 and monitored daily for development of EAE. The data shows significantly earlier onset, higher incidence of EAE in CX3CR1-deficient mice than in B6 mice. Data are presented as means ± SEM of at least four individual experiments (n ≥ 4), *P < 0.05.
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Figure 3: CX3CR1-deficient mice are more susceptible to EAE. CX3CR1gfp/gfp and B6 mice were immunized with (MOG)p35–55 and monitored daily for development of EAE. The data shows significantly earlier onset, higher incidence of EAE in CX3CR1-deficient mice than in B6 mice. Data are presented as means ± SEM of at least four individual experiments (n ≥ 4), *P < 0.05.

Mentions: Fractalkine receptor CX3CR1 and its ligand CX3CL1 are expressed within the CNS by microglia and neurons, respectively (29). Their interaction plays an important role in neurodevelopment and has also been implicated in neuroinflammation. Disruption of CX3CR1–CX3CL1 axis leads to microglial activation and hypersensitivity and may result in neurotoxicity [(18) and reviewed in Ref. (30)]. For instance, mice deficient in CX3CR1 have been reported to develop more severe EAE symptoms than WT animals (31). Here, we show that mice lacking CX3CR1 are more susceptible to EAE, with a significantly earlier onset and higher incidence of the disease (Figure 3). This data support conclusions from BM chimeras (31) that CX3CR1 regulates myeloid cell and possibly microglial responses, which in this case would act to dampen neuroinflammation, as also evidenced in CX3CR1-deficient mice (18).


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)

CX3CR1-deficient mice are more susceptible to EAE. CX3CR1gfp/gfp and B6 mice were immunized with (MOG)p35–55 and monitored daily for development of EAE. The data shows significantly earlier onset, higher incidence of EAE in CX3CR1-deficient mice than in B6 mice. Data are presented as means ± SEM of at least four individual experiments (n ≥ 4), *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: CX3CR1-deficient mice are more susceptible to EAE. CX3CR1gfp/gfp and B6 mice were immunized with (MOG)p35–55 and monitored daily for development of EAE. The data shows significantly earlier onset, higher incidence of EAE in CX3CR1-deficient mice than in B6 mice. Data are presented as means ± SEM of at least four individual experiments (n ≥ 4), *P < 0.05.
Mentions: Fractalkine receptor CX3CR1 and its ligand CX3CL1 are expressed within the CNS by microglia and neurons, respectively (29). Their interaction plays an important role in neurodevelopment and has also been implicated in neuroinflammation. Disruption of CX3CR1–CX3CL1 axis leads to microglial activation and hypersensitivity and may result in neurotoxicity [(18) and reviewed in Ref. (30)]. For instance, mice deficient in CX3CR1 have been reported to develop more severe EAE symptoms than WT animals (31). Here, we show that mice lacking CX3CR1 are more susceptible to EAE, with a significantly earlier onset and higher incidence of the disease (Figure 3). This data support conclusions from BM chimeras (31) that CX3CR1 regulates myeloid cell and possibly microglial responses, which in this case would act to dampen neuroinflammation, as also evidenced in CX3CR1-deficient mice (18).

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