bims-stacyt 2021-09-12 papers

Gene. 2020 Dec;pii: S2590-1583(20)30008-5. [Epub ahead of print]763S 100034

Glucose and TNF enhance expression of TNF and IL1B, and histone H3 acetylation and K4/K36 methylation, in juvenile macrophage cells.

Kazue Honma, Chie Machida, Kazuki Mochizuki, Toshinao Goda.

Hyperglycemia activates innate leukocytes such as monocytes and induces pro-inflammatory cytokine expression, resulting in increased monocyte adhesion to aortic endothelial cells. In this study, we investigated whether high glucose and/or tumor necrosis factor (TNF) would enhance pro-inflammatory cytokine expression of tumor necrosis factor (TNF) and interleukin (IL)-1β (IL1B) by altering histone modifications in U937, a juvenile macrophage cell line. The mRNA levels of TNF and IL1B in U937 cells were significantly affected by glucose concentration and TNF treatment. Mono-methylated histone H3K4 signals around TNF and IL1B were lower in cells treated with high glucose compared with low glucose. Conversely, tri-methylated histone H3K4 and H3K36 signals were higher in cells treated with high glucose compared with low glucose. TNF treatment of U937 cells cultured in high glucose enhanced histone H3K36 tri-methylation, particularly around the gene regions of TNF and IL1B. Histone acetylation was induced by treatment with TNF in high-glucose medium. The induction of acetylation and tri-methylation of K4 and K36 of histone H3 around TNF and IL1B by treatment with high glucose and/or TNF was positively associated with the induction of these genes in juvenile macrophage U937 cells.

Keywords: H3K36 methylation; H3K4 methylation; Histone acetylation; Juvenile macrophage; Pro-inflammatory cytokine; U937

DOI: https://doi.org/10.1016/j.gene.2020.100034

Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00366-1. [Epub ahead of print]33(9): 1883-1893.e7

Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype.

Emily Anderson-Baucum, Annie R Piñeros, Abhishek Kulkarni, Bobbie-Jo Webb-Robertson, Bernhard Maier, Ryan M Anderson, Wenting Wu, Sarah A Tersey, Teresa L Mastracci, Isabel Casimiro, Donalyn Scheuner, Thomas O Metz, Ernesto S Nakayasu, Carmella Evans-Molina, Raghavendra G Mirmira.

The metabolic inflammation (meta-inflammation) of obesity is characterized by proinflammatory macrophage infiltration into adipose tissue. Catalysis by deoxyhypusine synthase (DHPS) modifies the translation factor eIF5A to generate a hypusine (Hyp) residue. Hypusinated eIF5A (eIF5AHyp) controls the translation of mRNAs involved in inflammation, but its role in meta-inflammation has not been elucidated. Levels of eIF5AHyp were found to be increased in adipose tissue macrophages from obese mice and in murine macrophages activated to a proinflammatory M1-like state. Global proteomics and transcriptomics revealed that DHPS deficiency in macrophages altered the abundance of proteins involved in NF-κB signaling, likely through translational control of their respective mRNAs. DHPS deficiency in myeloid cells of obese mice suppressed M1 macrophage accumulation in adipose tissue and improved glucose tolerance. These findings indicate that DHPS promotes the post-transcriptional regulation of a subset of mRNAs governing inflammation and chemotaxis in macrophages and contributes to a proinflammatory M1-like phenotype.

Keywords: diabetes; hypusine; inflammation; mRNA translation; macrophage; obesity; polyamines; proteomics; transcriptomics

DOI: https://doi.org/10.1016/j.cmet.2021.08.003

Mol Med Rep. 2021 Nov;pii: 764. [Epub ahead of print]24(5):

High glucose‑induced upregulation of CD36 promotes inflammation stress via NF‑κB in H9c2 cells.

Baosheng Han, Jianzhong Wang, Jiawei Wu, Fang Yan, Yaru Wang, Jun Li.

Cardiac inflammation serves an important role in the progression of diabetic cardiomyopathy. CD36 (cluster of differentiation 36) mediates inflammation stress in a variety of disease states. The present study investigated CD36 expression in high glucose (HG)‑induced H9c2 cells, whether CD36 upregulation promotes inflammatory stress, and its potential mechanism. HG induced CD36 expression in a time‑dependent manner in cells, which was blocked following CD36 knockout or treatment with N‑acetylcysteine or MitoTEMPO. CD36 translocation to the cell membrane was increased at 72 h by HG stimulation of H9c2 cells. Moreover, CD36 knockout inhibited HG‑induced reactive oxygen species (ROS) generation, tumor necrosis factor‑α, interleukin (IL)‑6 and IL‑1β expression, and nuclear factor (NF)‑κB pathway activation. Further, CD36 knockout reversed metabolic reprogramming, lipid accumulation and AMP‑activated protein kinase activation caused by HG. The aforementioned data suggest that HG‑induced upregulation of CD36 promotes inflammatory stress via NF‑κB in H9c2 cells, mediated by metabolism reprogramming, lipid accumulation and enhanced ROS generation.

Keywords: CD36; H9c2 cells; diabetic cardiomyopathy; inflammation; reactive oxygen species

DOI: https://doi.org/10.3892/mmr.2021.12404

Front Oncol. 2021 ;11 685923

Targeting Adipokines in Obesity-Related Tumors.

Xi Pu, Deyu Chen.

Obesity, a global epidemic, is an independent risk factor for the occurrence and development of a variety of tumors, such as breast cancer, pancreatic cancer, ovarian cancer and colorectal cancer. Adipocytes are important endocrine cells in the tumor microenvironment of obesity-related tumors, which can secrete a variety of adipokines (such as leptin, adiponectin, estrogen, resistin, MIF and MCP-1, etc.), among which leptin, adiponectin and estrogen are the most in-depth and valuable ones. These adipokines are closely related to tumorigenesis and the progression of tumors. In recent years, more and more studies have shown that under chronic inflammatory conditions such as obesity, adipocytes secrete more adipokines to promote the tumorigenesis and development of tumors. However, it is worth noting that although adiponectin is also secreted by adipocytes, it has an anti-tumor effect, and can cross-talk with other adipokines (such as leptin and estrogen) and insulin to play an anti-tumor effect together. In addition, obesity is the main cause of insulin resistance, which can lead to the increase of the expression levels of insulin and insulin-like growth factor (IGF). As important regulators of blood glucose and lipid metabolism, insulin and IGF also play an important role in the progress of obesity related tumors. In view of the important role of adipokines secreted by adipocytes and insulin/IGF in tumors, this article not only elaborates leptin, adiponectin and estrogen secreted by adipocytes and their mechanism of action in the development of obesity- related tumors, but also introduces the relationship between insulin/IGF, a regulator of lipid metabolism, and obesity related tumors. At the same time, it briefly describes the cancer-promoting mechanism of resistin, MIF and MCP-1 in obesity-related tumors, and finally summarizes the specific treatment opinions and measures for various adipokines and insulin/insulin-like growth factors in recent years.

Keywords: adipocyte; adiponectin; estrogen; insulin; leptin; obesity

DOI: https://doi.org/10.3389/fonc.2021.685923

J Immunother Cancer. 2021 Sep;pii: e002787. [Epub ahead of print]9(9):

GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma.

BACKGROUND: A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies.
METHODS: We used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15 -/-, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression.
RESULTS: GDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse.
CONCLUSIONS: Our results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.

Keywords: biomarkers; immune tolerance; immunotherapy; tumor; tumor escape; tumor microenvironment

DOI: https://doi.org/10.1136/jitc-2021-002787

Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2102434118. [Epub ahead of print]118(37):

The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages.

Sri Murugan Poongkavithai Vadevoo, Gowri Rangaswamy Gunassekaran, ChaeEun Lee, NaHye Lee, Jiyoun Lee, Sehyun Chae, Jae-Yong Park, JaeHyung Koo, Byungheon Lee.

Expression and function of odorant receptors (ORs), which account for more than 50% of G protein-coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage-tumor axis. Using Olfr78 +/+ and Olfr78 -/- bone marrow-derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78-lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

Keywords: GPCR; OR51E2; Olfr78; TAMs; lactate

DOI: https://doi.org/10.1073/pnas.2102434118

Int J Mol Sci. 2021 Aug 31. pii: 9469. [Epub ahead of print]22(17):

IGF-1 and IGFBP-3 in Inflammatory Cachexia.

Ana Isabel Martín, Teresa Priego, Álvaro Moreno-Ruperez, Daniel González-Hedström, Miriam Granado, Asunción López-Calderón.

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic-growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic-GH-IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

Keywords: GH; IGF-1; IGFBP-3; cachexia; cytokines; glucocorticoids; inflammation; muscle wasting; nitric oxide; sepsis

DOI: https://doi.org/10.3390/ijms22179469