bims-meprid 2023-06-18 papers

Blood Adv. 2023 Jun 14. pii: bloodadvances.2023010083. [Epub ahead of print]

Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.

Dheerendra Gupta, Ahmed Elwakiel, Satish Ranjan, Manish Kumar Pandey, Shruthi Krishnan, Saira Ambreen, Reinhard Henschler, Rajiv Rana, Maria Keller, Uta Ceglarek, Khurrum Shahzad, Shrey Kohli, Berend Isermann.

A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. T-cell pre-incubation with aPC for 1 hour prior to transplantation increases FOXP3+ Tregs and reduces acute graft versus host disease (aGvHD) in mice, but the underlying mechanism remains unknown. As cellular metabolism modulates epigenetic gene regulation and plasticity in T-cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation and ex vivo using T-cells isolated from aGvHD mice without and with aPC preincubation or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of Th1-cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced TCA metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, while FOXP3 expression in splenic T-cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T-cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic marks, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype.

DOI: https://doi.org/10.1182/bloodadvances.2023010083

Cell Metab. 2023 Jun 08. pii: S1550-4131(23)00203-6. [Epub ahead of print]

Acetate controls endothelial-to-mesenchymal transition.

Endothelial-to-mesenchymal transition (EndMT), a process initiated by activation of endothelial TGF-β signaling, underlies numerous chronic vascular diseases and fibrotic states. Once induced, EndMT leads to a further increase in TGF-β signaling, thus establishing a positive-feedback loop with EndMT leading to more EndMT. Although EndMT is understood at the cellular level, the molecular basis of TGF-β-driven EndMT induction and persistence remains largely unknown. Here, we show that metabolic modulation of the endothelium, triggered by atypical production of acetate from glucose, underlies TGF-β-driven EndMT. Induction of EndMT suppresses the expression of the enzyme PDK4, which leads to an increase in ACSS2-dependent Ac-CoA synthesis from pyruvate-derived acetate. This increased Ac-CoA production results in acetylation of the TGF-β receptor ALK5 and SMADs 2 and 4 leading to activation and long-term stabilization of TGF-β signaling. Our results establish the metabolic basis of EndMT persistence and unveil novel targets, such as ACSS2, for the potential treatment of chronic vascular diseases.

Keywords: ACSS2; ALK5; PDK4; acetate; acetyl-CoA; atherosclerosis; endfothelial cells; endothelial-to-mesenchymal transition; transforming growth factor beta signaling

DOI: https://doi.org/10.1016/j.cmet.2023.05.010

Cancer Metastasis Rev. 2023 Jun 15.

Pancreatic cancer epigenetics: adaptive metabolism reprograms starving primary tumors for widespread metastatic outgrowth.

Arnaldo J Franco Torres, Jeffrey Duryea, Oliver G McDonald.

Pancreatic cancer is a paradigm for adaptation to extreme stress. That is because genetic drivers are selected during tissue injury with epigenetic imprints encoding wound healing responses. Ironically, epigenetic memories of trauma that facilitate neoplasia can also recreate past stresses to restrain malignant progression through symbiotic tumor:stroma crosstalk. This is best exemplified by positive feedback between neoplastic chromatin outputs and fibroinflammatory stromal cues that encase malignant glands within a nutrient-deprived desmoplastic stroma. Because epigenetic imprints are chemically encoded by nutrient-derived metabolites bonded to chromatin, primary tumor metabolism adapts to preserve malignant epigenetic fidelity during starvation. Despite these adaptations, stromal stresses inevitably awaken primordial drives to seek more hospitable climates. The invasive migrations that ensue facilitate entry into the metastatic cascade. Metastatic routes present nutrient-replete reservoirs that accelerate malignant progression through adaptive metaboloepigenetics. This is best exemplified by positive feedback between biosynthetic enzymes and nutrient transporters that saturate malignant chromatin with pro-metastatic metabolite byproducts. Here we present a contemporary view of pancreatic cancer epigenetics: selection of neoplastic chromatin under fibroinflammatory pressures, preservation of malignant chromatin during starvation stresses, and saturation of metastatic chromatin by nutritional excesses that fuel lethal metastasis.

Keywords: Cancer; Epigenetics; Metabolism; Metastasis; Pancreatic

DOI: https://doi.org/10.1007/s10555-023-10116-z

Nat Chem Biol. 2023 Jun 12.

Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation.

Lulu Chen, Qi Zhou, Pingfeng Zhang, Wei Tan, Yingge Li, Ziwen Xu, Junfeng Ma, Gary M Kupfer, Yanxin Pei, Qibin Song, Huadong Pei.

O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.

DOI: https://doi.org/10.1038/s41589-023-01354-x

Am J Physiol Cell Physiol. 2023 Jun 12.

Moderate exercise induces trained immunity in macrophages.

Mayoorey Murugathasan, Ardavan Jafari, Amandeep Amandeep, Syed A Hassan, Matthew Chihata, Ali A Abdul-Sater.

Despite its importance in protecting the host from infections and injury, excessive inflammation may lead to serious human diseases including autoimmune disorders, cardiovascular diseases, diabetes, and cancer. Exercise is a known immunomodulator; however, whether exercise causes long term changes in inflammatory responses and how these changes occur are lacking. Here, we show that chronic moderate intensity training of mice leads to persistent metabolic rewiring and changes to chromatin accessibility in bone marrow derived macrophages (BMDMs), which, in turn, tempers their inflammatory responses. We show that BMDMs from exercised mice exhibited a decrease in lipopolysaccharide (LPS) induced NF-kB activation and pro-inflammatory gene expression along with an increase in M2-like associated genes when compared to BMDMs from sedentary mice. This was associated with improved mitochondrial quality and increased reliance on oxidative phosphorylation accompanied with reduced mitochondrial ROS production. Mechanistically, ATAC-seq analysis showed changes in chromatin accessibility of genes associated with inflammatory and metabolic pathways. Overall, our data suggest that chronic moderate exercise can influence the inflammatory responses of macrophages by reprogramming their metabolic and epigenetic landscape.

Keywords: Exercise; Inflammation; Macrophages; Mitochondria; epigenetic

DOI: https://doi.org/10.1152/ajpcell.00130.2023