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Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection.

Xiao BG, Lu CZ, Link H - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis.Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration.Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. bgxiao@shmu.edu.cn

ABSTRACT
In the light of the enthusiasm to use of recombinant human granulocyte colony-stimulating factor (G-CSF) for immunomodulation and neuroprotection, it should be remembered that the current knowledge is based on a century of laborious research. G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis. Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration. Here, we describe the immunomodulation and the neuroprotection that can be achieved with G-CSF, and summarize possible mechanisms of G-CSF as a potential therapeutic agent in autoimmune diseases and neurological disorders. Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

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G-CSF-mediated neuroprotection in cerebral ischemia. (a-A) Survival rate of rats with cerebral ischemia treated with G-CSF and with saline as control, (a-B) Infarction volume and (a-C) Neurological Severity Score. (b) Double-labelled immunofluorescent staining of brain slices obtained from G-CSF-treated rats at day 7 after MCAO. Red images correspond to Brdu, GFAP or nestin and green images to fibronectin or BDNF.Yellow images reveal double-labelled positive cells. (c) G-CSF receptor expression in GFAP+ astrocytes in ischemic region (B), but not in non-ischemic region (A). Red images correspond to GFAP and green images to G-CSF receptor.Yellow images show double-labelled positive cells. (d) Area of cell death stained with PI (up) and number of bcl-2+ cells (down) at 7 days after hippocampal slice cultures in the absence (A) or presence (B) of G-CSF. (e) Expression of nestin, vWF and MAP-2 expression brain sections.The immunohistochemistry of nestin (A and B), vWF (C and D) and MAP-2 (E and F) are performed on brain slices obtained from G-CSF-treated rats and control rats at day 7 after MCAO.
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fig02: G-CSF-mediated neuroprotection in cerebral ischemia. (a-A) Survival rate of rats with cerebral ischemia treated with G-CSF and with saline as control, (a-B) Infarction volume and (a-C) Neurological Severity Score. (b) Double-labelled immunofluorescent staining of brain slices obtained from G-CSF-treated rats at day 7 after MCAO. Red images correspond to Brdu, GFAP or nestin and green images to fibronectin or BDNF.Yellow images reveal double-labelled positive cells. (c) G-CSF receptor expression in GFAP+ astrocytes in ischemic region (B), but not in non-ischemic region (A). Red images correspond to GFAP and green images to G-CSF receptor.Yellow images show double-labelled positive cells. (d) Area of cell death stained with PI (up) and number of bcl-2+ cells (down) at 7 days after hippocampal slice cultures in the absence (A) or presence (B) of G-CSF. (e) Expression of nestin, vWF and MAP-2 expression brain sections.The immunohistochemistry of nestin (A and B), vWF (C and D) and MAP-2 (E and F) are performed on brain slices obtained from G-CSF-treated rats and control rats at day 7 after MCAO.

Mentions: The upregulation of G-CSF was accompanied by a more modest induction of the G-CSF receptor after cerebral ischemia, more prominent in the ipsilateral than the contralateral hemisphere [53]. Immunohistochemistry demonstrated the co-expression and up-regulation of G-CSF and its receptor in neurons after MCAO and reperfusion. In human acute ischemic stroke, strong neuronal G-CSF receptor expression was encountered in the infarct area and the peri-infarct rim as compared to the contralateral cortex. In subacute infarctions, microglial G-CSF receptor predominated, whereas chronic infarction was characterized by the presence of G-CSF receptor-expressing reactive astrocytes [62]. We observed that G-CSF receptor was expressed in glial fibrillary acidic protein (GFAP)+ astrocytes in ischemic regions, but not in non-ischemic regions (Fig. 2c, unpublished data), revealing that G-CSF and its receptor likely function as an autocrine adaptive system within the CNS.


Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection.

Xiao BG, Lu CZ, Link H - J. Cell. Mol. Med. (2007 Nov-Dec)

G-CSF-mediated neuroprotection in cerebral ischemia. (a-A) Survival rate of rats with cerebral ischemia treated with G-CSF and with saline as control, (a-B) Infarction volume and (a-C) Neurological Severity Score. (b) Double-labelled immunofluorescent staining of brain slices obtained from G-CSF-treated rats at day 7 after MCAO. Red images correspond to Brdu, GFAP or nestin and green images to fibronectin or BDNF.Yellow images reveal double-labelled positive cells. (c) G-CSF receptor expression in GFAP+ astrocytes in ischemic region (B), but not in non-ischemic region (A). Red images correspond to GFAP and green images to G-CSF receptor.Yellow images show double-labelled positive cells. (d) Area of cell death stained with PI (up) and number of bcl-2+ cells (down) at 7 days after hippocampal slice cultures in the absence (A) or presence (B) of G-CSF. (e) Expression of nestin, vWF and MAP-2 expression brain sections.The immunohistochemistry of nestin (A and B), vWF (C and D) and MAP-2 (E and F) are performed on brain slices obtained from G-CSF-treated rats and control rats at day 7 after MCAO.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401293&req=5

fig02: G-CSF-mediated neuroprotection in cerebral ischemia. (a-A) Survival rate of rats with cerebral ischemia treated with G-CSF and with saline as control, (a-B) Infarction volume and (a-C) Neurological Severity Score. (b) Double-labelled immunofluorescent staining of brain slices obtained from G-CSF-treated rats at day 7 after MCAO. Red images correspond to Brdu, GFAP or nestin and green images to fibronectin or BDNF.Yellow images reveal double-labelled positive cells. (c) G-CSF receptor expression in GFAP+ astrocytes in ischemic region (B), but not in non-ischemic region (A). Red images correspond to GFAP and green images to G-CSF receptor.Yellow images show double-labelled positive cells. (d) Area of cell death stained with PI (up) and number of bcl-2+ cells (down) at 7 days after hippocampal slice cultures in the absence (A) or presence (B) of G-CSF. (e) Expression of nestin, vWF and MAP-2 expression brain sections.The immunohistochemistry of nestin (A and B), vWF (C and D) and MAP-2 (E and F) are performed on brain slices obtained from G-CSF-treated rats and control rats at day 7 after MCAO.
Mentions: The upregulation of G-CSF was accompanied by a more modest induction of the G-CSF receptor after cerebral ischemia, more prominent in the ipsilateral than the contralateral hemisphere [53]. Immunohistochemistry demonstrated the co-expression and up-regulation of G-CSF and its receptor in neurons after MCAO and reperfusion. In human acute ischemic stroke, strong neuronal G-CSF receptor expression was encountered in the infarct area and the peri-infarct rim as compared to the contralateral cortex. In subacute infarctions, microglial G-CSF receptor predominated, whereas chronic infarction was characterized by the presence of G-CSF receptor-expressing reactive astrocytes [62]. We observed that G-CSF receptor was expressed in glial fibrillary acidic protein (GFAP)+ astrocytes in ischemic regions, but not in non-ischemic regions (Fig. 2c, unpublished data), revealing that G-CSF and its receptor likely function as an autocrine adaptive system within the CNS.

Bottom Line: G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis.Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration.Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. bgxiao@shmu.edu.cn

ABSTRACT
In the light of the enthusiasm to use of recombinant human granulocyte colony-stimulating factor (G-CSF) for immunomodulation and neuroprotection, it should be remembered that the current knowledge is based on a century of laborious research. G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis. Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration. Here, we describe the immunomodulation and the neuroprotection that can be achieved with G-CSF, and summarize possible mechanisms of G-CSF as a potential therapeutic agent in autoimmune diseases and neurological disorders. Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.

Show MeSH
Related in: MedlinePlus