P572Granulocyte-colony-stimulating-factor attenuates the inflammatory response after experimental stroke by suppressing dendritic cell functions

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Abstract

Purpose

Stroke, as an implication of atherosclerosis, provokes an inflammatory cascade in the infarcted brain, which is assumed to secondarily worsen the ischemic tissue damage. Being able to induce immune stimulation or tolerance, dendritic cells (DC) are important regulators of the immune system. To explore their role on the inflammatory response in the course of stroke, the growth factor G-CSF was used to modulate DC-mediated immune processes.

Methods

Cerebral ischemia was introduced in male Wistar rats by means of transient middle cerebral artery occlusion (tMCAO), followed by G-CSF application in a single and repetitive mode of treatment. Silver staining was used for the detection of the infarct size. Migration of DCs (Ox62) and further inflammatory cells was quantified using immunohistochemical staining. Quantitative real-time PCR served to determine the mRNA levels of TLRs (TLR2, TLR4) and co-stimulatory molecules (CD83, CD86), to analyze the maturation of brain-migrated antigen-presenting cells and transcription rates of inflammation-associated cytokines. Besides, the effects on peripheral T-cell specific immune responses were measured by flow cytometry.

Results

G-CSF led to a reduction of the infarct size and an improved neurological outcome. Neuroprotective effects of G-CSF were associated with a decreased migration of CD86 expressing cells, while DC migration was only reduced after the single application of G-CSF. Apart from that, decreased mRNA levels of all TLRs and co-stimulatory molecules, accounted for an inhibited activation and maturation of DCs and further antigen-presenting-cells induced by G-CSF. Suppressed DC maturation-state correlated with an inhibition of stroke-induced T-cell proliferation in the spleen and a decreased activation of T-lymphocytes in peripheral blood. These findings were associated with an increased cerebral transcription rate of the anti-inflammatory cytokine IL-10 together with a reduced transcription of IFN-y after the application of G-CSF, which demonstrates a regression of cerebral inflammation following stroke.

Conclusions

Our results suggest DCs to play a pivotal role in the regulation of stroke-induced inflammation. Neuroprotective effects of G-CSF are associated with a suppressed maturation of brain-migrated DCs, which results in an inhibition of T-cell specific immune responses and an attenuated inflammatory state of the infarcted brain.

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