The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia

Nature Communications
Han Seok KohEun Jung Park

Abstract

Inflammation is closely related to the extent of damage following cerebral ischaemia, and the targeting of this inflammation has emerged as a promising therapeutic strategy. Here, we present that hypoxia-induced glial T-cell immunoglobulin and mucin domain protein (TIM)-3 can function as a modulator that links inflammation and subsequent brain damage after ischaemia. We find that TIM-3 is highly expressed in hypoxic brain regions of a mouse cerebral hypoxia-ischaemia (H/I) model. TIM-3 is distinctively upregulated in activated microglia and astrocytes, brain resident immune cells, in a hypoxia-inducible factor (HIF)-1-dependent manner. Notably, blockade of TIM-3 markedly reduces infarct size, neuronal cell death, oedema formation and neutrophil infiltration in H/I mice. Hypoxia-triggered neutrophil migration and infarction are also decreased in HIF-1α-deficient mice. Moreover, functional neurological deficits after H/I are significantly improved in both anti-TIM-3-treated mice and myeloid-specific HIF-1α-deficient mice. Further understanding of these insights could serve as the basis for broadening the therapeutic scope against hypoxia-associated brain diseases.

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Citations

Oct 4, 2017·Nature Reviews. Immunology·Cormac T Taylor, Sean P Colgan
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Methods Mentioned

BETA
FACS
immunoprecipitation
flow cytometry
transfection
PCR

Software Mentioned

Image J
LigthCycler 480 Quantification
Treestar
ARRIVE
CellQuest
SigmaPlot
FlowJo
Image J analyser
NIH Image J

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