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Review
. 2007 Nov-Dec;11(6):1272-90.
doi: 10.1111/j.1582-4934.2007.00101.x.

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

Bao-Guo Xiao  1 , Chuan-Zhen Lu, Hans Link
Affiliations
Review

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

Bao-Guo Xiao et al. J Cell Mol Med. 2007 Nov-Dec.

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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Figures

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Possible mechanisms of immunomodulation of G-CSF in adaptive immunity.G-CSF induces the expression of both GATA-3 and SOCS3, which control T helper cell differentiation, and directs to Th2 response. G-CSF directly induces the generation of tolerogenic DC, or indirectly drives the production of tolerogenic DC through inducing SOCS3 expression.Tolerogenic DC have the capacity to induce a regulatory T cells or/and Th2 immune responses. Despite our limited knowledge about the molecular mechanisms involved, it is clear that G-CSF treatment results in increase in the number of regulatory T cells and the differentiation of Th2 cells. G-CSF-induced SOCS3 in turn limits G-CSF receptor signalling.
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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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Possible mechanisms for neuroprotection of G-CSF in cerebral ischemia and neurodegeneration. G-CSF provokes multiple intracellular signal transductions including Jak/Stat, ERK and PI3K/Akt in neuroprotection. (1) Anti-apoptosis: G-CSF mediates antiapoptotic pathway through ERK or/and JAK/Stat signalling activation and subsequent upregulation of bcl-2 and inhibition of caspase- 3; (2) Neuronal differentiation: Stat regulates VEGF expression, or G-CSF activates endothelial cells to release BDNF.VEGF, BDNF and activated PI3K/Akt promote neurogenesis (3) Angiogenesis: G-CSF stimulates neutrophils or astrocytes to secrete VEGF, or directly mobilizes circulating endothelial progenitor cells (cEPCs) to promote angiogenesis within the CNS; and (4) The mobilization of autologous hemopoietic stem cells: G-CSF triggers the mobilization of autologous hemopoietic stem cells that migrate into ischemic brain, and thus significantly improve lesion repair.
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Possible mechanisms for G-CSF-mediated neuroprotection via immunomodulation. G-CSF polarizes T cell differentiation from Th1 to Th2 cells and induces Th2 responses, or relies on tolerogenic DC to generate regulatory T cells, which can enter into the CNS to contribute to the neuroprotective microenvironment through producing BDNF, IL-4, IL-10 and TGF-b. In addition, G-CSF, as an anti-inflammatory agent, can reduce levels of IFN-γ, IL-1β, IL-6, TNF-α and iNOS production in order to co-construct the neuroprotective microenvironment.
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