Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice

Egle Cekanaviciute, Nancy Fathali, Kristian Doyle, Aaron M. Williams, Jullet Han, Marion S. Buckwalter

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Astrocytes limit inflammation after CNS injury, at least partially by physically containing it within an astrocytic scar at the injury border. We report here that astrocytic transforming growth factor-beta (TGFβ) signaling is a second, distinct mechanism that astrocytes utilize to limit neuroinflammation. TGFβs are anti-inflammatory and neuroprotective cytokines that are upregulated subacutely after stroke, during a clinically accessible time window. We have previously demonstrated that TGFβs signal to astrocytes, neurons and microglia in the stroke border days after stroke. To investigate whether TGFβ affects astrocyte immunoregulatory functions, we engineered "Ast-Tbr2DN" mice where TGFβ signaling is inhibited specifically in astrocytes. Despite having a similar infarct size to wildtype controls, Ast-Tbr2DN mice exhibited significantly more neuroinflammation during the subacute period after distal middle cerebral occlusion (dMCAO) stroke. The peri-infarct cortex of Ast-Tbr2DN mice contained over 60% more activated CD11b+ monocytic cells and twice as much immunostaining for the activated microglia and macrophage marker CD68 than controls. Astrocytic scarring was not altered in Ast-Tbr2DN mice. However, Ast-Tbr2DN mice were unable to upregulate TGF-β1 and its activator thrombospondin-1 2 days after dMCAO. As a result, the normal upregulation of peri-infarct TGFβ signaling was blunted in Ast-Tbr2DN mice. In this setting of lower TGFβ signaling and excessive neuroinflammation, we observed worse motor outcomes and late infarct expansion after photothrombotic motor cortex stroke. Taken together, these data demonstrate that TGFβ signaling is a molecular mechanism by which astrocytes limit neuroinflammation, activate TGFβ in the peri-infarct cortex and preserve brain function during the subacute period after stroke. GLIA 2014;62:1227-1240 Main points: Astrocytic TGFβ signaling is a critical pathway for limiting subacute neuroinflammation in peri-infarct cortex after stroke. Mice with inhibited astrocytic TGFβ signaling exhibited excessive neuroinflammation, failed to upregulate TGFβ, and developed worse motor deficits after stroke.

Original languageEnglish (US)
Pages (from-to)1227-1240
Number of pages14
JournalGLIA
Volume62
Issue number8
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Transforming Growth Factor beta
Stroke
Astrocytes
Up-Regulation
Microglia
Cicatrix
Thrombospondin 1
Critical Pathways
Wounds and Injuries
Motor Cortex
Anti-Inflammatory Agents
Macrophages
Cytokines
Inflammation
Neurons
Brain

Keywords

  • Astrocytes
  • Cytokines
  • Immunity
  • Inflammation
  • Ischemia

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Medicine(all)

Cite this

Cekanaviciute, E., Fathali, N., Doyle, K., Williams, A. M., Han, J., & Buckwalter, M. S. (2014). Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. GLIA, 62(8), 1227-1240. https://doi.org/10.1002/glia.22675

Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. / Cekanaviciute, Egle; Fathali, Nancy; Doyle, Kristian; Williams, Aaron M.; Han, Jullet; Buckwalter, Marion S.

In: GLIA, Vol. 62, No. 8, 2014, p. 1227-1240.

Research output: Contribution to journalArticle

Cekanaviciute, E, Fathali, N, Doyle, K, Williams, AM, Han, J & Buckwalter, MS 2014, 'Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice', GLIA, vol. 62, no. 8, pp. 1227-1240. https://doi.org/10.1002/glia.22675
Cekanaviciute, Egle ; Fathali, Nancy ; Doyle, Kristian ; Williams, Aaron M. ; Han, Jullet ; Buckwalter, Marion S. / Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. In: GLIA. 2014 ; Vol. 62, No. 8. pp. 1227-1240.
@article{980a4a79ccb942b8a5234cda551ba2b9,
title = "Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice",
abstract = "Astrocytes limit inflammation after CNS injury, at least partially by physically containing it within an astrocytic scar at the injury border. We report here that astrocytic transforming growth factor-beta (TGFβ) signaling is a second, distinct mechanism that astrocytes utilize to limit neuroinflammation. TGFβs are anti-inflammatory and neuroprotective cytokines that are upregulated subacutely after stroke, during a clinically accessible time window. We have previously demonstrated that TGFβs signal to astrocytes, neurons and microglia in the stroke border days after stroke. To investigate whether TGFβ affects astrocyte immunoregulatory functions, we engineered {"}Ast-Tbr2DN{"} mice where TGFβ signaling is inhibited specifically in astrocytes. Despite having a similar infarct size to wildtype controls, Ast-Tbr2DN mice exhibited significantly more neuroinflammation during the subacute period after distal middle cerebral occlusion (dMCAO) stroke. The peri-infarct cortex of Ast-Tbr2DN mice contained over 60{\%} more activated CD11b+ monocytic cells and twice as much immunostaining for the activated microglia and macrophage marker CD68 than controls. Astrocytic scarring was not altered in Ast-Tbr2DN mice. However, Ast-Tbr2DN mice were unable to upregulate TGF-β1 and its activator thrombospondin-1 2 days after dMCAO. As a result, the normal upregulation of peri-infarct TGFβ signaling was blunted in Ast-Tbr2DN mice. In this setting of lower TGFβ signaling and excessive neuroinflammation, we observed worse motor outcomes and late infarct expansion after photothrombotic motor cortex stroke. Taken together, these data demonstrate that TGFβ signaling is a molecular mechanism by which astrocytes limit neuroinflammation, activate TGFβ in the peri-infarct cortex and preserve brain function during the subacute period after stroke. GLIA 2014;62:1227-1240 Main points: Astrocytic TGFβ signaling is a critical pathway for limiting subacute neuroinflammation in peri-infarct cortex after stroke. Mice with inhibited astrocytic TGFβ signaling exhibited excessive neuroinflammation, failed to upregulate TGFβ, and developed worse motor deficits after stroke.",
keywords = "Astrocytes, Cytokines, Immunity, Inflammation, Ischemia",
author = "Egle Cekanaviciute and Nancy Fathali and Kristian Doyle and Williams, {Aaron M.} and Jullet Han and Buckwalter, {Marion S.}",
year = "2014",
doi = "10.1002/glia.22675",
language = "English (US)",
volume = "62",
pages = "1227--1240",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

TY - JOUR

T1 - Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice

AU - Cekanaviciute, Egle

AU - Fathali, Nancy

AU - Doyle, Kristian

AU - Williams, Aaron M.

AU - Han, Jullet

AU - Buckwalter, Marion S.

PY - 2014

Y1 - 2014

N2 - Astrocytes limit inflammation after CNS injury, at least partially by physically containing it within an astrocytic scar at the injury border. We report here that astrocytic transforming growth factor-beta (TGFβ) signaling is a second, distinct mechanism that astrocytes utilize to limit neuroinflammation. TGFβs are anti-inflammatory and neuroprotective cytokines that are upregulated subacutely after stroke, during a clinically accessible time window. We have previously demonstrated that TGFβs signal to astrocytes, neurons and microglia in the stroke border days after stroke. To investigate whether TGFβ affects astrocyte immunoregulatory functions, we engineered "Ast-Tbr2DN" mice where TGFβ signaling is inhibited specifically in astrocytes. Despite having a similar infarct size to wildtype controls, Ast-Tbr2DN mice exhibited significantly more neuroinflammation during the subacute period after distal middle cerebral occlusion (dMCAO) stroke. The peri-infarct cortex of Ast-Tbr2DN mice contained over 60% more activated CD11b+ monocytic cells and twice as much immunostaining for the activated microglia and macrophage marker CD68 than controls. Astrocytic scarring was not altered in Ast-Tbr2DN mice. However, Ast-Tbr2DN mice were unable to upregulate TGF-β1 and its activator thrombospondin-1 2 days after dMCAO. As a result, the normal upregulation of peri-infarct TGFβ signaling was blunted in Ast-Tbr2DN mice. In this setting of lower TGFβ signaling and excessive neuroinflammation, we observed worse motor outcomes and late infarct expansion after photothrombotic motor cortex stroke. Taken together, these data demonstrate that TGFβ signaling is a molecular mechanism by which astrocytes limit neuroinflammation, activate TGFβ in the peri-infarct cortex and preserve brain function during the subacute period after stroke. GLIA 2014;62:1227-1240 Main points: Astrocytic TGFβ signaling is a critical pathway for limiting subacute neuroinflammation in peri-infarct cortex after stroke. Mice with inhibited astrocytic TGFβ signaling exhibited excessive neuroinflammation, failed to upregulate TGFβ, and developed worse motor deficits after stroke.

AB - Astrocytes limit inflammation after CNS injury, at least partially by physically containing it within an astrocytic scar at the injury border. We report here that astrocytic transforming growth factor-beta (TGFβ) signaling is a second, distinct mechanism that astrocytes utilize to limit neuroinflammation. TGFβs are anti-inflammatory and neuroprotective cytokines that are upregulated subacutely after stroke, during a clinically accessible time window. We have previously demonstrated that TGFβs signal to astrocytes, neurons and microglia in the stroke border days after stroke. To investigate whether TGFβ affects astrocyte immunoregulatory functions, we engineered "Ast-Tbr2DN" mice where TGFβ signaling is inhibited specifically in astrocytes. Despite having a similar infarct size to wildtype controls, Ast-Tbr2DN mice exhibited significantly more neuroinflammation during the subacute period after distal middle cerebral occlusion (dMCAO) stroke. The peri-infarct cortex of Ast-Tbr2DN mice contained over 60% more activated CD11b+ monocytic cells and twice as much immunostaining for the activated microglia and macrophage marker CD68 than controls. Astrocytic scarring was not altered in Ast-Tbr2DN mice. However, Ast-Tbr2DN mice were unable to upregulate TGF-β1 and its activator thrombospondin-1 2 days after dMCAO. As a result, the normal upregulation of peri-infarct TGFβ signaling was blunted in Ast-Tbr2DN mice. In this setting of lower TGFβ signaling and excessive neuroinflammation, we observed worse motor outcomes and late infarct expansion after photothrombotic motor cortex stroke. Taken together, these data demonstrate that TGFβ signaling is a molecular mechanism by which astrocytes limit neuroinflammation, activate TGFβ in the peri-infarct cortex and preserve brain function during the subacute period after stroke. GLIA 2014;62:1227-1240 Main points: Astrocytic TGFβ signaling is a critical pathway for limiting subacute neuroinflammation in peri-infarct cortex after stroke. Mice with inhibited astrocytic TGFβ signaling exhibited excessive neuroinflammation, failed to upregulate TGFβ, and developed worse motor deficits after stroke.

KW - Astrocytes

KW - Cytokines

KW - Immunity

KW - Inflammation

KW - Ischemia

UR - http://www.scopus.com/inward/record.url?scp=84902345621&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902345621&partnerID=8YFLogxK

U2 - 10.1002/glia.22675

DO - 10.1002/glia.22675

M3 - Article

C2 - 24733756

AN - SCOPUS:84902345621

VL - 62

SP - 1227

EP - 1240

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 8

ER -