Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 4, 2025

Trained immunity refers to the long-term memory of innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution tricarboxylic acid (TCA) cycle and enhance cytokine production monocytes. Our experiments demonstrate monocytes preferentially employe lactate over as a TCA substrate, metabolism required for cell responses bacterial fungal infection. Except cycle, endogenous or exogenous also supports by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, CUT&Tag-seq chromatin accessibility in manner dependent Inhibiting lactate-dependent silencing dehydrogenase A (LDHA) impairs both fueled These findings suggest hub immunometabolic epigenetic programs

Language: Английский

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Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Oct. 24, 2022

Abstract Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary model, we find enzyme fatty acid 2-hydroxylase (FA2H), which catalyzes hydroxylation free acids (FAs), enriched subpopulation ESCC with high metastatic potential, FA2H knockdown markedly mitigates lesions. Moreover, increased expression positively associated poor survival patients ESCC. Lipidomics analysis identifies two dihydroceramides—Cer(d18:0/24:0) Cer(d18:0/24:1)—are FA2H-depleted metastasizing cells. Upon administration, Cer(d18:0/24:0) Cer(d18:0/24:1) impair formation overt metastases mouse experimental model. Then, forkhead box protein C2 (FOXC2) are found be co-upregulated populations specimens, further experimentally verified transcriptionally induced by FOXC2, boosted per se tumour necrosis factor α (TNFα), critical pro-metastasis cytokine microenvironment, Together, these results demonstrate TNFα-FOXC2-FA2H novel signaling axis promote metastasis, its downstream dihydroceramide products could promising drugs intervene metastasis.

Language: Английский

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CD8+ T cell metabolic rewiring defined by scRNA-seq identifies a critical role of ASNS expression dynamics in T cell differentiation

Cell Reports, Journal Year: 2022, Volume and Issue: 41(7), P. 111639 - 111639

Published: Nov. 1, 2022

T cells dynamically rewire their metabolism during an immune response. We applied single-cell RNA sequencing to CD8+ activated and differentiated in vitro physiological medium resolve these metabolic dynamics. identify a differential time-dependent reliance of activating on the synthesis versus uptake various non-essential amino acids, which we corroborate with functional assays. also genes that potentially dictate outcome cell differentiation, by ranking them based expression Among them, find asparagine synthetase (Asns), whose peaks for effector decays toward memory formation. Disrupting dynamics ASNS overexpression promotes phenotype, enhancing anti-tumor response adoptively transferred mouse melanoma model. thus provide resource dynamic changes activation as modulator differentiation.

Language: Английский

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Aldolase A Accelerates Cancer Progression by Modulating mRNA Translation and Protein Biosynthesis via Noncanonical Mechanisms

Advanced Science, Journal Year: 2023, Volume and Issue: 10(26)

Published: July 11, 2023

Abstract Aldolase A (ALDOA), a crucial glycolytic enzyme, is often aberrantly expressed in various types of cancer. Although ALDOA has been reported to play additional roles beyond its conventional enzymatic role, nonmetabolic function and underlying mechanism cancer progression remain elusive. Here, it shown that promotes liver growth metastasis by accelerating mRNA translation independent catalytic activity. Mechanistically, interacted with insulin‐ like factor 2 mRNA‐binding protein 1 (IGF2BP1) facilitate binding m 6 A‐modified eIF4G mRNA, thereby increasing levels subsequently enhancing overall biosynthesis cells. Importantly, administration GalNAc‐conjugated siRNA targeting effectively slows the tumor orthotopic xenografts. Collectively, these findings uncover previously unappreciated modulating highlight potential specifically as prospective therapeutic strategy

Language: Английский

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GLUT3 promotes macrophage signaling and function via RAS-mediated endocytosis in atopic dermatitis and wound healing

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(21)

Published: Sept. 18, 2023

The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that expression increased after M1 polarization stimuli found M2 stimulation macrophages. Conditional deletion of Glut3 (LysM-Cre Glut3fl/fl) impaired bone marrow-derived Alternatively activated macrophages from the skin patients with atopic dermatitis showed expression, a calcipotriol-induced model was rescued LysM-Cre Glut3fl/fl mice. M2-like human wound tissues as assessed by transcriptomics costaining, significantly decreased nonhealing, compared healing, diabetic foot ulcers. In an excisional healing model, mice macrophage delayed healing. promoted IL-4/STAT6 signaling, independently its glucose transport activity. Unlike plasma membrane-localized GLUT1, localized primarily to endosomes required for efficient endocytosis IL-4Rα subunits. interacted directly GTP-bound RAS vitro vivo through intracytoplasmic loop domain, this interaction STAT6 activation polarization. PAK macropinocytosis were also without GLUT3, suggesting broader roles regulation endocytosis. Thus, is alternative function, transport-independent, RAS-mediated role activation.

Language: Английский

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