bims-stacyt 2020-07-19 papers

Arch Physiol Biochem. 2020 Jul 13. 1-8

Protection of leukemia inhibitory factor against high-glucose-induced human retinal endothelial cell dysfunction.

Lei Wang, Qiong Wu, Rui Qi Wang, Run Ze Wang, Jianwen Wang.

PURPOSE: In the study, we aimed to explore the mechanism of leukaemia inhibitory factor (LIF) affects hyperglycaemic induced retinopathy by regulating CaMKII-CREB pathway.METHODS: Human retinal endothelial cell (HRECs) induced by high glucose to simulate one of the pathogenesis in the diabetic retinopathy (DR) model. After LIF treatment, cell viability was detected by CCK-8 and apoptosis was detected by flow cytometry. Angiogenesis was detected by in vitro tube formation. The expression levels of inflammatory, angiogenesis related proteins and CaMKII-CREB were detected by western blot. The gene level of angiogenesis was detected by qRT-PCR. HE staining was used to detect pathological changes of retinopathy in diabetic mice after LIF treatment.
RESULTS: Our results showed that LIF significantly increased hyperglycaemic-induced cell viability and inhibited apoptosis. Western blot results showed that LIF could down-regulate the expression levels of inflammatory cytokines such as IL-1β, IL-6 and TNF-α. In addition, angiogenesis of HRECs was inhibited by LIF in tubulisation experiments. LIF can down-regulate protein and gene levels of VEGF and HIF-1α via western blot and qRT-PCR. In diabetic mice induced by STZ, LIF could down-regulate the protein level of VEGF, HIF-1α, p-CaMKII and p-CREB, which suggest that LIF could inhibit retinal angiogenesis in diabetic mice. The results of HE staining showed that LIF could alleviate the damage of retinopathy in diabetic mice.
CONCLUSION: LIF could alleviate the damage of diabetic retinopathy by modulating the CaMKII/CREB signalling pathway to inhibit inflammatory response and angiogenesis.

Keywords: HRECs; Leukaemia inhibitory factor (LIF); angiogenesis; diabetic retinopathy (DR)

DOI: https://doi.org/10.1080/13813455.2020.1792506

Cell Mol Life Sci. 2020 Jul 11.

Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance.

Fang Wei, Dan Wang, Junyuan Wei, Niwen Tang, Le Tang, Fang Xiong, Can Guo, Ming Zhou, Xiaoling Li, Guiyuan Li, Wei Xiong, Shanshan Zhang, Zhaoyang Zeng.

The successful treatment of human cancers by immunotherapy has been made possible by breakthroughs in the discovery of immune checkpoint regulators, including CTLA-4 and PD-1/PD-L1. However, the immunosuppressive effect of the tumor microenvironment still represents an important bottleneck that limits the success of immunotherapeutic approaches. The tumor microenvironment influences the metabolic crosstalk between tumor cells and tumor-infiltrating immune cells, creating competition for the utilization of nutrients and promoting immunosuppression. In addition, tumor-derived metabolites regulate the activation and effector function of immune cells through a variety of mechanisms; in turn, the metabolites and other factors secreted by immune cells can also become accomplices to cancer development. Immune-metabolic checkpoint regulation is an emerging concept that is being studied with the aim of restoring the immune response in the tumor microenvironment. In this review, we summarize the metabolic reprogramming of various cell types present in the tumor microenvironment, with a focus on the interaction between the metabolic pathways of these cells and antitumor immunosuppression. We also discuss the main metabolic checkpoints that could provide new means of enhancing antitumor immunotherapy.

Keywords: Antitumor immunotherapy; Immune checkpoint; Metabolic checkpoint; Metabolic reprogramming; Tumor metabolism

DOI: https://doi.org/10.1007/s00018-020-03581-0

Nat Commun. 2020 Jul 15. 11(1): 3547

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling.

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.

DOI: https://doi.org/10.1038/s41467-020-17402-2