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Article ; Online: Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition.

Zeng, Cheng / Chen, Jiwei / Cooke, Emmalee W / Subuddhi, Arijita / Roodman, Eliana T / Chen, Fei Xavier / Cao, Kaixiang

2023 Volume 14, Issue 1, Page(s) 4944

Abstract: The major enhancer regulator lysine-specific histone demethylase 1A (LSD1) is required for mammalian embryogenesis and is implicated in human congenital diseases and multiple types of cancer; however, the underlying mechanisms remain enigmatic. Here, we ... ...

Abstract	The major enhancer regulator lysine-specific histone demethylase 1A (LSD1) is required for mammalian embryogenesis and is implicated in human congenital diseases and multiple types of cancer; however, the underlying mechanisms remain enigmatic. Here, we dissect the role of LSD1 and its demethylase activity in gene regulation and cell fate transition. Surprisingly, the catalytic inactivation of LSD1 has a mild impact on gene expression and cellular differentiation whereas the loss of LSD1 protein de-represses enhancers globally and impairs cell fate transition. LSD1 deletion increases H3K27ac levels and P300 occupancy at LSD1-targeted enhancers. The gain of H3K27ac catalyzed by P300/CBP, not the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss. Together, our study demonstrates a demethylase-independent role of LSD1 in regulating enhancers and cell fate transition, providing insight into treating diseases driven by LSD1 mutations and misregulation.
MeSH term(s)	Humans ; Animals ; Cell Differentiation ; Regulatory Sequences, Nucleic Acid ; Embryo, Mammalian ; Catalysis ; Histone Demethylases/genetics ; Mammals
Chemical Substances	Histone Demethylases (EC 1.14.11.-)
Language	English
Publishing date	2023-08-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40606-1
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Article ; Online: The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.

Pai, Chun-Peng / Wang, Han / Seachrist, Darcie D / Agarwal, Neel / Adams, Joshua A / Liu, Zhenghao / Keri, Ruth A / Cao, Kaixiang / Schiemann, William P / Kao, Hung-Ying

Cell death and differentiation

2024

Abstract: The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its ... ...

Abstract	The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER+ breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1, KLF4, YAP1, SNAI1, and MYC. Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML-depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Significantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer, and offer new insights into the unique roles of PML isoforms in breast cancer.
Language	English
Publishing date	2024-04-16
Publishing country	England
Document type	Journal Article
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-024-01294-6
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Integrated waveguide coupled ultralow-loss multimode waveguides based on silicon nitride resonators.

Cui, Shuai / Yu, Yuan / Cao, Kaixiang / Pan, Zhao / Gao, Xiaoyan / Zhang, Xinliang

Optics express

2021 Volume 32, Issue 2, Page(s) 2179–2187

Abstract: On-chip micro-ring resonators (MRRs) with low loss and large free spectral ranges (FSRs) are important for photonic devices. So far, ultra-low-loss silicon-nitride (Si3N4) waveguides are primarily fabricated in laboratories, as they often demand special ... ...

Abstract	On-chip micro-ring resonators (MRRs) with low loss and large free spectral ranges (FSRs) are important for photonic devices. So far, ultra-low-loss silicon-nitride (Si3N4) waveguides are primarily fabricated in laboratories, as they often demand special processes to reduce transmission losses. While, Si3N4 waveguides fabricated by the standard multi-project wafer (MPW)-based processes often suffer from significant sidewall scattering, resulting in high scattering losses. Here, we present an innovative approach to photonics by introducing a compact and multi-mode structure. This approach significantly reduces the contact between the optical field and the rough sidewalls in the high-confinement Si3N4 waveguide. By incorporating modified Euler bends, and a weakly tapered gap directional coupler, adiabatic transmission with simultaneous ultra-low loss and compact size is achieved even in 7-µm wide waveguide. Results show that the intrinsic quality factor Qi of MRR is (6.8 ± 0.4) × 10
Language	English
Publishing date	2021-10-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1491859-6
ISSN	1094-4087 ; 1094-4087
ISSN (online)	1094-4087
ISSN	1094-4087
DOI	10.1364/OE.507791
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Article ; Online: Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Huang, Shu-Qi / Cao, Kai-Xiang / Wang, Cai-Ling / Chen, Pei-Ling / Chen, Yi-Xin / Zhang, Yu-Ting / Yu, Shi-Hui / Bai, Zai-Xia / Guo, Shuai / Liao, Mu-Xi / Li, Qiao-Wen / Zhang, Guo-Qi / He, Jun / Xu, Yi-Ming

Acta pharmacologica Sinica

2024

Abstract: Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are ... ...

Abstract	Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 μM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/s41401-024-01262-3
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Article ; Online: Endothelial NLRP3 inflammasome regulation in atherosclerosis.

Guo, Shuai / Wang, Litao / Cao, Kaixiang / Li, Ziling / Song, Mingchuan / Huang, Shuqi / Li, Zou / Wang, Cailing / Chen, Peiling / Wang, Yong / Dai, Xiaoyan / Chen, Xianglin / Fu, Xiaodong / Feng, Du / He, Jun / Huo, Yuqing / Xu, Yiming

Cardiovascular research

2024

Abstract: Aim: The activation of Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in endothelial cells (ECs) contributes to vascular inflammation in atherosclerosis. Considering the high glycolytic rate of ECs, we delineated ... ...

Abstract	Aim: The activation of Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in endothelial cells (ECs) contributes to vascular inflammation in atherosclerosis. Considering the high glycolytic rate of ECs, we delineated whether and how glycolysis determines endothelial NLRP3 inflammasome activation in atherosclerosis. Methods and results: Our results demonstrated a significant upregulation of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), a key regulator of glycolysis, in human and mouse atherosclerotic endothelium, which positively correlated with NLRP3 levels. Atherosclerotic stimuli upregulated endothelial PFKFB3 expression via sterol regulatory element binding protein 2 (SREBP2) transactivation. EC-selective haplodeficiency of Pfkfb3 in Apoe-/- mice resulted in reduced endothelial NLRP3 inflammasome activation and attenuation of atherogenesis. Mechanistic investigations revealed that PFKFB3-driven glycolysis increased the NADH content and induced oligomerization of C-terminal binding protein 1 (CtBP1), an NADH-sensitive transcriptional co-repressor. The monomer form, but not the oligomer form, of CtBP1 was found to associate with the transcriptional repressor Forkhead box P1 (FOXP1) and acted as a transrepressor of inflammasome components, including NLRP3, caspase-1, and interleukin-1β (IL-1β). Interfering with NADH-induced CtBP1 oligomerization restored its binding to FOXP1 and inhibited the glycolysis-dependent upregulation of NLRP3, Caspase-1, and IL-1β. Additionally, EC-specific overexpression of NADH-insensitive CtBP1 alleviates atherosclerosis. Conclusions: Our findings highlight the existence of a glycolysis-dependent NADH/CtBP/FOXP1-transrepression pathway that regulates endothelial NLRP3 inflammasome activation in atherogenesis. This pathway represents a potential target for selective PFKFB3 inhibitors or strategies aimed at disrupting CtBP1 oligomerization to modulate atherosclerosis.
Language	English
Publishing date	2024-04-16
Publishing country	England
Document type	Journal Article
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvae071
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Zs.A 565: Show issues

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Article ; Online: Glycolysis Promotes Angiotensin II-Induced Aortic Remodeling Through Regulating Endothelial-to-Mesenchymal Transition via the Corepressor C-Terminal Binding Protein 1.

Wang, Litao / Guo, Shuai / Cao, Kaixiang / Li, Ziling / Li, Zou / Song, Mingchuan / Wang, Cailing / Chen, Peiling / Cui, Ying / Dai, Xiaoyan / Feng, Du / Fu, Xiaodong / He, Jun / Xu, Yiming

Hypertension (Dallas, Tex. : 1979)

2023 Volume 80, Issue 12, Page(s) 2627–2640

Abstract: Background: Endothelial dysfunction plays a crucial role in aortic remodeling. Aerobic glycolysis and endothelial-to-mesenchymal transition (EndoMT) have, respectively, been suggested to contribute to endothelial dysfunction in many cardiovascular ... ...

Abstract	Background: Endothelial dysfunction plays a crucial role in aortic remodeling. Aerobic glycolysis and endothelial-to-mesenchymal transition (EndoMT) have, respectively, been suggested to contribute to endothelial dysfunction in many cardiovascular diseases. Here, we tested the hypothesis that glycolytic reprogramming is critical for EndoMT induction in aortic remodeling through an epigenetic mechanism mediated by a transcriptional corepressor CtBP1 (C-terminal binding protein 1), a sensor of glycolysis-derived NADH. Methods: EndoMT program, aortic remodeling, and endothelial expression of the glycolytic activator PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3) were evaluated in Ang (angiotensin) II-infused mice. Mice with endothelial-specific Results: The EndoMT program and increased endothelial PFKFB3 expression were induced in remodeled thoracic aortas. In TGF-β (transforming growth factor-β)-treated human endothelial cells, activated SMAD2/3 (SMAD Family Member 2/3) transcriptionally upregulated PFKFB3 expression. In turn, the TGF-β/SMAD signaling and EndoMT were compromised by silencing or inhibition of PFKFB3. Mechanistic studies revealed that PFKFB3-mediated glycolysis increased NADH content and activated the NADH-sensitive CtBP1. Through interaction with the transcription repressor E2F4 (E2F Transcription Factor 4), CtBP1 enhanced E2F4-mediated transcriptional repression of SMURF2 (SMAD ubiquitin regulatory factor 2), a negative regulator of TGF-β/SMAD2 signaling. Additionally, EC-specific Conclusions: Our results demonstrate a glycolysis-mediated positive feedback loop of the TGF-β signaling to induce EndoMT and indicate that therapeutically targeting endothelial PFKFB3 or CtBP1 activity could provide a basis for treating EndoMT-linked aortic remodeling.
MeSH term(s)	Mice ; Humans ; Animals ; Endothelial Cells/metabolism ; Angiotensin II/pharmacology ; Angiotensin II/metabolism ; NAD/metabolism ; Transcription Factors/metabolism ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta/metabolism ; Glycolysis ; Aorta/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	C-terminal binding protein (EC 1.1.1.-) ; Angiotensin II (11128-99-7) ; NAD (0U46U6E8UK) ; Transcription Factors ; Transforming Growth Factor beta ; SMURF2 protein, human (EC 2.3.2.26) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.123.21382
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Article ; Online: Inhibit globally, act locally: CDK7 inhibitors in cancer therapy.

Cao, Kaixiang / Shilatifard, Ali

Cancer cell

2014 Volume 26, Issue 2, Page(s) 158–159

Abstract: Cyclin-dependent kinases (CDKs) are involved in temporal control of the cell cycle and transcription and play central roles in cancer development and metastasis. Recently, Kwiatkowski and colleagues identified a novel CDK7-specific inhibitor, THZ1, that ... ...

Abstract	Cyclin-dependent kinases (CDKs) are involved in temporal control of the cell cycle and transcription and play central roles in cancer development and metastasis. Recently, Kwiatkowski and colleagues identified a novel CDK7-specific inhibitor, THZ1, that hinders proliferation in cancer cell lines and dampens global transcription in T cell leukemia.
MeSH term(s)	Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Phenylenediamines/pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/enzymology ; Pyrimidines/pharmacology
Chemical Substances	Enzyme Inhibitors ; Phenylenediamines ; Pyrimidines
Language	English
Publishing date	2014-08-11
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccr.2014.07.020
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.

Zhao, Zibo / Cao, Kaixiang / Watanabe, Jun / Philips, Cassandra N / Zeidner, Jacob M / Ishi, Yukitomo / Wang, Qixuan / Gold, Sarah R / Junkins, Katherine / Bartom, Elizabeth T / Yue, Feng / Chandel, Navdeep S / Hashizume, Rintaro / Ben-Sahra, Issam / Shilatifard, Ali

The Journal of clinical investigation

2023 Volume 133, Issue 13

Abstract: Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we ... ...

Abstract	Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.
MeSH term(s)	Humans ; Animals ; Mice ; Proteomics ; Histone-Lysine N-Methyltransferase/genetics ; Mutation ; Neoplasms/genetics ; Epigenesis, Genetic
Chemical Substances	Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; MLL4 protein, mouse (EC 2.1.1.43)
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI169993
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Article ; Online: Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.

Cao, Kaixiang / Zhang, Tiejun / Li, Zou / Song, Mingchuan / Li, Anqi / Yan, Jingwei / Guo, Shuai / Wang, Litao / Huang, Shuqi / Li, Ziling / Hou, Wenzhong / Dai, Xiaoyan / Wang, Yong / Feng, Du / He, Jun / Fu, Xiaodong / Xu, Yiming

The Journal of pathology

2023 Volume 259, Issue 4, Page(s) 388–401

Abstract: Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid ... ...

Abstract	Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing Pfkfb3 had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel de novo fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.
MeSH term(s)	Mice ; Humans ; Animals ; Hyperplasia/pathology ; Muscle, Smooth, Vascular/pathology ; Vascular System Injuries ; Cell Proliferation ; Neointima/pathology ; Cell Movement ; Cells, Cultured ; Disease Models, Animal ; Phenotype ; Fatty Acids/metabolism ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mechanistic Target of Rapamycin Complex 1/pharmacology ; Myocytes, Smooth Muscle/pathology
Chemical Substances	Fatty Acids ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2023-02-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6052
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Article ; Online: Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells.

Yan, Jingwei / Li, Anqi / Chen, Xianglin / Cao, Kaixiang / Song, Mingchuan / Guo, Shuai / Li, Zou / Huang, Shuqi / Li, Ziling / Xu, Danghan / Wang, Yong / Dai, Xiaoyan / Feng, Du / Huo, Yuqing / He, Jun / Xu, Yiming

Pharmacological research

2022 Volume 179, Page(s) 106208

Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which are immunosuppressive and glycolytically inactive in inflammatory diseases. However, it is unknown whether MDSCs contribute to ischemic stroke and how ...

Abstract	Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which are immunosuppressive and glycolytically inactive in inflammatory diseases. However, it is unknown whether MDSCs contribute to ischemic stroke and how glycolysis regulates MDSC function in such a context. Here, we showed that MDSCs arise in the blood of patients at early phase of stroke. Similar results were observed in temporary middle cerebral artery occlusion-induced cerebral ischemic mice. Pharmaceutical exhaustion of MDSCs aggravated, while adoptive transfer of MDSCs rescued the ischemic brain injury. However, the differentiation of MDSCs into immunopotent myeloid cells which coincides with increased glycolysis was observed in the context of ischemic stroke. Mechanistically, the glycolytic product lactate autonomously induces MDSC differentiation through activation of mTORC1, and paracrinely activates Th1 and Th17 cells. Moreover, gene knockout or inhibition of the glycolytic enzyme PFKFB3 increased endogenous MDSCs by blocking their differentiation, and improved ischemic brain injury. Collectively, these results revealed that glycolytic switch decreases the immunosuppressive and neuroprotective role of MDSCs in ischemic stroke and pharmacological targeting MDSCs via glycolysis inhibition constitutes a promising therapeutic strategy for ischemic stroke.
MeSH term(s)	Animals ; Brain Injuries ; Glycolysis ; Humans ; Immunosuppressive Agents ; Ischemic Stroke ; Mice ; Mice, Inbred C57BL ; Myeloid-Derived Suppressor Cells
Chemical Substances	Immunosuppressive Agents
Language	English
Publishing date	2022-04-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2022.106208
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