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.
Highlights
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
We suggest that expression of T-cell immunoglobulin and mucin domain protein (TIM)-3 on microglia and astrocytes is upregulated under hypoxia, and that this enhancement influences the infiltration of neutrophils into the hypoxic penumbra
We found that transcript levels of T-cell immunoglobulin and mucin domain-3 (TIM-3) were notably higher in ipsilateral penumbra compared with contralateral regions
Summary
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. Cerebral ischaemia triggers a complex cascade of pathophysiological changes that lead to brain injury, in the penumbral area surrounding the ischaemic core[1,2] These alterations include the activation of resident cells, production of inflammatory mediators and infiltration of inflammatory cells. We suggest that expression of TIM-3 on microglia and astrocytes is upregulated under hypoxia, and that this enhancement influences the infiltration of neutrophils into the hypoxic penumbra Such infiltration has been identified as a main cause of ischaemic brain damage[5,34]. Our results suggest that hypoxia-induced glial TIM-3 may be an important molecular player in inflammation-associated brain injury under hypoxic conditions These insights into the link between inflammation and ischaemic brain injury improve our understanding of the functions of glial TIM-3 and HIF-1, and may contribute to the development of new therapeutic strategies for cerebral ischaemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
