title: The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia.
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.
authors: 1] Cancer Immunology Branch, Department of System Cancer Science, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea [2] Department of Life Science, Hallym University, Chuncheon 200-702, Republic of Korea.
authors: Han Seok
authors: HS
authors: Koh
authors: Cancer Immunology Branch, Department of System Cancer Science, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea.
authors: Chi Young
authors: CY
authors: Chang
authors: Cancer Immunology Branch, Department of System Cancer Science, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea.
authors: Sae-Bom
authors: SB
authors: Jeon
authors: Cancer Immunology Branch, Department of System Cancer Science, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea.
authors: Hee Jung
authors: HJ
authors: Yoon
authors: Cancer Immunology Branch, Department of System Cancer Science, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea.
authors: Ye-Hyeon
authors: YH
authors: Ahn
authors: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 410-769, Republic of Korea.
authors: Hyung-Seok
authors: HS
authors: Kim
authors: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 410-769, Republic of Korea.
authors: In-Hoo
authors: IH
authors: Kim
authors: Department of Life Science, Hallym University, Chuncheon 200-702, Republic of Korea.
authors: Sung Ho
authors: SH
authors: Jeon
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EG Cambridge, UK.
authors: Randall S
authors: RS
authors: Johnson
authors: 1] Cancer Immunology Branch, Department of System Cancer Science, National Cancer Center, 111 jungbalsan-ro, Kyunggi 410-769, Republic of Korea [2] Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 410-769, Republic of Korea.
authors: Eun Jung
authors: EJ
authors: Park
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D001921:Brain / Q000276:immunology* / Q000473:pathology; D017536:Carotid Artery, Common / Q000601:surgery; D002465:Cell Movement; D002478:Cells, Cultured; D000072597:Hepatitis A Virus Cellular Receptor 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation; D008026:Ligation; D008279:Magnetic Resonance Imaging; D008636:Mesencephalon; D051379:Mice; D017628:Microglia / Q000276:immunology*; D009457:Neuroglia / Q000276:immunology; D009504:Neutrophils; D012333:RNA, Messenger / Q000378:metabolism*; D011991:Receptors, Virus / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011991:Receptors, Virus