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

Han Seok Koh, Chi Young Chang, Sae-Bom Jeon, Hee Jung Yoon, Ye-Hyeon Ahn, Hyung-Seok Kim, In-Hoo Kim, Sung Ho Jeon, Randall S. Johnson and Eun Jung Park ()
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Han Seok Koh: Cancer Immunology Branch, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea
Chi Young Chang: Cancer Immunology Branch, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea
Sae-Bom Jeon: Cancer Immunology Branch, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea
Hee Jung Yoon: Cancer Immunology Branch, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea
Ye-Hyeon Ahn: Cancer Immunology Branch, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea
Hyung-Seok Kim: Graduate School of Cancer Science and Policy, National Cancer Center
In-Hoo Kim: Graduate School of Cancer Science and Policy, National Cancer Center
Sung Ho Jeon: Hallym University
Randall S. Johnson: Development and Neuroscience, University of Cambridge
Eun Jung Park: Cancer Immunology Branch, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7340

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