Limits...
Astrocyte regulation of CNS inflammation and remyelination.

Claycomb KI, Johnson KM, Winokur PN, Sacino AV, Crocker SJ - Brain Sci (2013)

Bottom Line: We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies.Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain.In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. ijichi@student.uchc.edu.

ABSTRACT
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.

No MeSH data available.


Related in: MedlinePlus

Widespread astrogliosis is a prominent neuropathological feature of the twitcher mouse brain. Representative pictures show immunohistochemically labeled glial fibrillary acidic protein (GFAP)+ astrocytes (red) in several regions of the brain, including cerebellum, midbrain, thalamus, and cortex in wildtype C57BL/6 (upper row) and in age-matched twitcher mice (bottom row). Note that highly fibrous GFAP immunoreactivity is observed with greater intensity throughout the twitcher mouse brain, compared to wildtype mouse. Scare bar = 250 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061872&req=5

brainsci-03-01109-f001: Widespread astrogliosis is a prominent neuropathological feature of the twitcher mouse brain. Representative pictures show immunohistochemically labeled glial fibrillary acidic protein (GFAP)+ astrocytes (red) in several regions of the brain, including cerebellum, midbrain, thalamus, and cortex in wildtype C57BL/6 (upper row) and in age-matched twitcher mice (bottom row). Note that highly fibrous GFAP immunoreactivity is observed with greater intensity throughout the twitcher mouse brain, compared to wildtype mouse. Scare bar = 250 μm.

Mentions: We have recently implicated astrocytes in the pathogenesis of neuropathology in GLD. We determined that astrocytic expression of matrix metalloproteinase (MMP)-3, an extracellular protease, is dramatically increased at the time of clinical disease onset in the twitcher mice. Furthermore, its expression continues to elevate with disease progression [86]. This astrocytic MMP-3, which potentially targets myelin protein proteolytically, is a primary mediator of the formation of multinucleated globoid cells, highly activated phagocytes and a hallmark of GLD pathology [86]. In addition, it was reported that the production of hematopoietic prostaglandin synthase (HPGDS) and PGD2 in microglia is significantly increased along with elevated expression of astrocytic PGD2 receptors, DP1 and DP2 [87]. Pharmacological blockade of HPGDS or genetic ablation of DP1 in the twitcher mouse resulted in decreased astrogliosis and microgliosis, accompanying by less demyelination [87]. Thus, astrocytic reactivity in the CNS of GLD may not represent a secondary response to demyelination, but rather may be a primary response to accumulated psychosine in this disease that may contribute significantly to the pathogenesis of GLD (Figure 1). Further study on the regulation of astrocyte reactivity in this disease may represent a new avenue for understanding the etiology of neuropathology in GLD.


Astrocyte regulation of CNS inflammation and remyelination.

Claycomb KI, Johnson KM, Winokur PN, Sacino AV, Crocker SJ - Brain Sci (2013)

Widespread astrogliosis is a prominent neuropathological feature of the twitcher mouse brain. Representative pictures show immunohistochemically labeled glial fibrillary acidic protein (GFAP)+ astrocytes (red) in several regions of the brain, including cerebellum, midbrain, thalamus, and cortex in wildtype C57BL/6 (upper row) and in age-matched twitcher mice (bottom row). Note that highly fibrous GFAP immunoreactivity is observed with greater intensity throughout the twitcher mouse brain, compared to wildtype mouse. Scare bar = 250 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061872&req=5

brainsci-03-01109-f001: Widespread astrogliosis is a prominent neuropathological feature of the twitcher mouse brain. Representative pictures show immunohistochemically labeled glial fibrillary acidic protein (GFAP)+ astrocytes (red) in several regions of the brain, including cerebellum, midbrain, thalamus, and cortex in wildtype C57BL/6 (upper row) and in age-matched twitcher mice (bottom row). Note that highly fibrous GFAP immunoreactivity is observed with greater intensity throughout the twitcher mouse brain, compared to wildtype mouse. Scare bar = 250 μm.
Mentions: We have recently implicated astrocytes in the pathogenesis of neuropathology in GLD. We determined that astrocytic expression of matrix metalloproteinase (MMP)-3, an extracellular protease, is dramatically increased at the time of clinical disease onset in the twitcher mice. Furthermore, its expression continues to elevate with disease progression [86]. This astrocytic MMP-3, which potentially targets myelin protein proteolytically, is a primary mediator of the formation of multinucleated globoid cells, highly activated phagocytes and a hallmark of GLD pathology [86]. In addition, it was reported that the production of hematopoietic prostaglandin synthase (HPGDS) and PGD2 in microglia is significantly increased along with elevated expression of astrocytic PGD2 receptors, DP1 and DP2 [87]. Pharmacological blockade of HPGDS or genetic ablation of DP1 in the twitcher mouse resulted in decreased astrogliosis and microgliosis, accompanying by less demyelination [87]. Thus, astrocytic reactivity in the CNS of GLD may not represent a secondary response to demyelination, but rather may be a primary response to accumulated psychosine in this disease that may contribute significantly to the pathogenesis of GLD (Figure 1). Further study on the regulation of astrocyte reactivity in this disease may represent a new avenue for understanding the etiology of neuropathology in GLD.

Bottom Line: We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies.Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain.In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. ijichi@student.uchc.edu.

ABSTRACT
Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.

No MeSH data available.


Related in: MedlinePlus