Repository logo
 

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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Koh, Han Seok 
Chang, Chi Young 
Jeon, Sae-Bom 
Yoon, Hee Jung 
Ahn, Ye-Hyeon 

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.

Description

Keywords

Animals, Astrocytes, Brain, Carotid Artery, Common, Cell Movement, Cells, Cultured, Hepatitis A Virus Cellular Receptor 2, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Ischemia, Brain, Immunohistochemistry, In Vitro Techniques, Inflammation, Ligation, Magnetic Resonance Imaging, Mesencephalon, Mice, Microglia, Neuroglia, Neutrophils, RNA, Messenger, Receptors, Virus, Reverse Transcriptase Polymerase Chain Reaction

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

6

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (092738/Z/10/Z)