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Monocyte chemoattractant protein-1-deficiency impairs the expression of IL-6, IL-1β and G-CSF after transient focal ischemia in mice.

Strecker JK, Minnerup J, Gess B, Ringelstein EB, Schäbitz WR, Schilling M - PLoS ONE (2011)

Bottom Line: Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells.Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia.These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Münster, Münster, Germany. strecker.jan@gmx.de

ABSTRACT
Monocyte chemoattractant protein-1 (MCP-1), a chemokine secreted by neurons and astrocytes following stroke is known to aggravate ischemia-related damage. Previous studies revealed that MCP-1-deficient mice develop smaller infarcts and have an improved neurological outcome, whereas mice overexpressing MCP-1 show worsened brain damage and impaired neurological function. The aim of the present study was to elucidate the molecular background of the enhanced recovery in MCP-1-deficient mice after stroke. For this purpose, we (1) performed expression analyses on crucial post-stroke related inflammatory genes in MCP-1-deficient mice compared to wildtype controls, (2) analyzed a possible impact of MCP-1 on astrocyte activation (3) investigated the cellular origin of respective inflammatory cytokines and (4) analyzed the impact of MCP-1 secretion on the migration of both neutrophil granulocytes and T-cells. Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells. Additionally, MCP-1-deficient mice developed smaller infarcts 36 hours after experimental stroke. Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia. These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.

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MCP-1-deficiency leads to an impaired influx of neutrophil granulocytes and T-cells.(A) Quantitative assessment of migrated neutrophils within ipsilateral cortex (cor, fig.1 A) following 30 min transient middle cerebral artery occlusion. Values are obtained counting the absolute number of cortical 7/4-positive cells in 8 sections per animal. Twelve hours after MCAO, MCP-1-deficient mice showed an impaired influx of neutrophil granulocytes within the ipsilateral cortex compared to wildtype controls (*p<0.001). (B) Quantitative analysis of T-cell migration within the ipsilateral cortex of MCP-1-deficient and wildtype mice. Thirty-six hours after MCAO T-cell numbers were significantly lower in MCP-1-deficient animals. (C) Immunohistochemistry of neutrophil granulocytes within the ipsilateral cortex. Representative 7/4 stained image taken from a wildtype animal. Following transient cerebral ischemia most neutrophil granulocytes were found within the meningeal layers and the cortical tissue. Scale bar = 100 µm. (D) T-cell within the ipsilateral cortex of a wildtype mouse. Arrowheads mark the border of a blood vessel. Nuclear counterstain with DAPI (blue). Scale bar = 25 µm.
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pone-0025863-g006: MCP-1-deficiency leads to an impaired influx of neutrophil granulocytes and T-cells.(A) Quantitative assessment of migrated neutrophils within ipsilateral cortex (cor, fig.1 A) following 30 min transient middle cerebral artery occlusion. Values are obtained counting the absolute number of cortical 7/4-positive cells in 8 sections per animal. Twelve hours after MCAO, MCP-1-deficient mice showed an impaired influx of neutrophil granulocytes within the ipsilateral cortex compared to wildtype controls (*p<0.001). (B) Quantitative analysis of T-cell migration within the ipsilateral cortex of MCP-1-deficient and wildtype mice. Thirty-six hours after MCAO T-cell numbers were significantly lower in MCP-1-deficient animals. (C) Immunohistochemistry of neutrophil granulocytes within the ipsilateral cortex. Representative 7/4 stained image taken from a wildtype animal. Following transient cerebral ischemia most neutrophil granulocytes were found within the meningeal layers and the cortical tissue. Scale bar = 100 µm. (D) T-cell within the ipsilateral cortex of a wildtype mouse. Arrowheads mark the border of a blood vessel. Nuclear counterstain with DAPI (blue). Scale bar = 25 µm.

Mentions: As a result of oxygen deprivation and subsequent expression of chemokines and cytokines, various hematogenous cells are attracted into the ischemic tissue and influence the subsequent inflammatory response. In this study, we analyzed whether the altered expression of IL-6, IL-1β and G-CSF in MCP-1-deficient mice has an influence on the post-stroke migration of neutrophil granulocytes and T-cells. For this purpose, we counted and compared the numbers of migrated neutrophil granulocytes and T-cells within the ipsilateral cortex of wildtype and MCP-1-deficient mice. We detected an accumulation of 7/4-positive cells within the ipsilateral cortex and the meningeal layers in both examined groups of animals (Fig.6 C). Cell number analysis revealed a reduced influx of neutrophil granulocytes in MCP-1-deficient mice 12 hours following MCAO (p<0.001, Fig.6 A). Twelve hours after cerebral ischemia few T-cells could be seen in both wildtype and MCP-1-deficient mice. The majority of detected T-cells seemed to be in close vicinity to blood vessels or attached to the respective endothelium (Fig.6 D). Quantitative analyses revealed a significant difference 36 hours after MCAO as T-cell numbers increased in wildtype but not MCP-1-deficient mice (p<0.01).


Monocyte chemoattractant protein-1-deficiency impairs the expression of IL-6, IL-1β and G-CSF after transient focal ischemia in mice.

Strecker JK, Minnerup J, Gess B, Ringelstein EB, Schäbitz WR, Schilling M - PLoS ONE (2011)

MCP-1-deficiency leads to an impaired influx of neutrophil granulocytes and T-cells.(A) Quantitative assessment of migrated neutrophils within ipsilateral cortex (cor, fig.1 A) following 30 min transient middle cerebral artery occlusion. Values are obtained counting the absolute number of cortical 7/4-positive cells in 8 sections per animal. Twelve hours after MCAO, MCP-1-deficient mice showed an impaired influx of neutrophil granulocytes within the ipsilateral cortex compared to wildtype controls (*p<0.001). (B) Quantitative analysis of T-cell migration within the ipsilateral cortex of MCP-1-deficient and wildtype mice. Thirty-six hours after MCAO T-cell numbers were significantly lower in MCP-1-deficient animals. (C) Immunohistochemistry of neutrophil granulocytes within the ipsilateral cortex. Representative 7/4 stained image taken from a wildtype animal. Following transient cerebral ischemia most neutrophil granulocytes were found within the meningeal layers and the cortical tissue. Scale bar = 100 µm. (D) T-cell within the ipsilateral cortex of a wildtype mouse. Arrowheads mark the border of a blood vessel. Nuclear counterstain with DAPI (blue). Scale bar = 25 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198727&req=5

pone-0025863-g006: MCP-1-deficiency leads to an impaired influx of neutrophil granulocytes and T-cells.(A) Quantitative assessment of migrated neutrophils within ipsilateral cortex (cor, fig.1 A) following 30 min transient middle cerebral artery occlusion. Values are obtained counting the absolute number of cortical 7/4-positive cells in 8 sections per animal. Twelve hours after MCAO, MCP-1-deficient mice showed an impaired influx of neutrophil granulocytes within the ipsilateral cortex compared to wildtype controls (*p<0.001). (B) Quantitative analysis of T-cell migration within the ipsilateral cortex of MCP-1-deficient and wildtype mice. Thirty-six hours after MCAO T-cell numbers were significantly lower in MCP-1-deficient animals. (C) Immunohistochemistry of neutrophil granulocytes within the ipsilateral cortex. Representative 7/4 stained image taken from a wildtype animal. Following transient cerebral ischemia most neutrophil granulocytes were found within the meningeal layers and the cortical tissue. Scale bar = 100 µm. (D) T-cell within the ipsilateral cortex of a wildtype mouse. Arrowheads mark the border of a blood vessel. Nuclear counterstain with DAPI (blue). Scale bar = 25 µm.
Mentions: As a result of oxygen deprivation and subsequent expression of chemokines and cytokines, various hematogenous cells are attracted into the ischemic tissue and influence the subsequent inflammatory response. In this study, we analyzed whether the altered expression of IL-6, IL-1β and G-CSF in MCP-1-deficient mice has an influence on the post-stroke migration of neutrophil granulocytes and T-cells. For this purpose, we counted and compared the numbers of migrated neutrophil granulocytes and T-cells within the ipsilateral cortex of wildtype and MCP-1-deficient mice. We detected an accumulation of 7/4-positive cells within the ipsilateral cortex and the meningeal layers in both examined groups of animals (Fig.6 C). Cell number analysis revealed a reduced influx of neutrophil granulocytes in MCP-1-deficient mice 12 hours following MCAO (p<0.001, Fig.6 A). Twelve hours after cerebral ischemia few T-cells could be seen in both wildtype and MCP-1-deficient mice. The majority of detected T-cells seemed to be in close vicinity to blood vessels or attached to the respective endothelium (Fig.6 D). Quantitative analyses revealed a significant difference 36 hours after MCAO as T-cell numbers increased in wildtype but not MCP-1-deficient mice (p<0.01).

Bottom Line: Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells.Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia.These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Münster, Münster, Germany. strecker.jan@gmx.de

ABSTRACT
Monocyte chemoattractant protein-1 (MCP-1), a chemokine secreted by neurons and astrocytes following stroke is known to aggravate ischemia-related damage. Previous studies revealed that MCP-1-deficient mice develop smaller infarcts and have an improved neurological outcome, whereas mice overexpressing MCP-1 show worsened brain damage and impaired neurological function. The aim of the present study was to elucidate the molecular background of the enhanced recovery in MCP-1-deficient mice after stroke. For this purpose, we (1) performed expression analyses on crucial post-stroke related inflammatory genes in MCP-1-deficient mice compared to wildtype controls, (2) analyzed a possible impact of MCP-1 on astrocyte activation (3) investigated the cellular origin of respective inflammatory cytokines and (4) analyzed the impact of MCP-1 secretion on the migration of both neutrophil granulocytes and T-cells. Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells. Additionally, MCP-1-deficient mice developed smaller infarcts 36 hours after experimental stroke. Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia. These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.

Show MeSH
Related in: MedlinePlus