Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4+ T cells in the synovial fluid (SF) of affected joints. JIA CD4+ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4+ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4+ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.

Juvenile Idiopathic Arthritis (JIA) describes a heterogeneous group of autoimmune conditions with an unknown cause and childhood onset. It is characterized by the accumulation of mononuclear cells, notably activated CD4+ memory/effector T (Tmem/Teff) cells, within the synovial fluid of affected joints. JIA CD4+ T cells exhibit a unique epigenomic signature linked to inflammation, however, the molecular mechanisms driving this remain unclear. Here we show that CD4+ T cells isolated from JIA synovial fluid (SF) exhibit abnormal intracellular metabolism marked by heightened glycolysis after activation driving transcriptional reprogramming. Epigenetic profiling between activated healthy controls and JIA patients allowed the definition of specific disease-related enhancers upregulated in SF-derived JIA CD4+ T cells. Pharmacological inhibition of glycolytic flux affected the expression of genes associated with these enhancers. When activated in the presence of JIA SF, CD4+ T cells obtained from healthy control (HC) subjects, displayed heightened glycolytic activity compared to paired plasma. Moreover, this also led to increased H3K27ac at JIA-specific genes. Increased H3K27ac was dependent on glycolytic flux, but not oxidative phosphorylation. Inhibition of glycolysis also specifically affected the transcription of genes upregulated during T cell activation in the presence of SF. Inhibiting the glycolytic enzyme pyruvate dehydrogenase (PDH) reduced JIA-associated gene expression. Taken together, these findings demonstrate that for JIA, the inflammatory microenvironment can modulate T cell activation-driven transcriptional programs through a glycolysis-mediated pathway. Specific targeting of this T cell metabolism-epigenetic axis may provide avenues for intervention during the development of autoinflammatory disease.

Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR-31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

INTRODUCTION:To decrease antibiotic resistance, their use as growth promoters in the agricultural sector has been largely abandoned. This may lead to decreased health due to infectious disease or microbiome changes leading to gut inflammation.OBJECTIVES:We aimed to generate a m/z signature classifying chicken health in blood, and obtain biological insights from the resulting m/z signature.METHODS:We used direct infusion mass-spectrometry to determine a machine-learned metabolomics signature that classifies chicken health from a blood sample. We then challenged the resulting models by investigating the classification capability of the signature on novel data obtained at poultry houses in previously unseen countries using a Leave-One-Country-Out (LOCO) cross-validation strategy. Additionally, we optimised the number of mass/charge (m/z) values required to maximise the classification capability of Random Forest models, by developing a novel ranking system based on combined univariate t-test and fold-change analyses and building models based on this ranking through forward and reverse feature selection.RESULTS:The multi-country and LOCO models could classify chicken health. Both resulting 25-m/z and 3784-m/z signatures reliably classified chicken health in multiple countries. Through mummichog enrichment analysis on the large m/z signature, we found changes in amino acid metabolism, including branched chain amino acids and polyamines.CONCLUSION:We reliably classified chicken health from blood, independent of genetic-, farm-, feed- and country-specific confounding factors. The 25-m/z signature can be used to aid development of a per-metabolite panel. The extended 3784-m/z version can be used to gain a deeper understanding of the metabolic causes and consequences of low chicken health. Together, they may facilitate future treatment, prevention and intervention.

Psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Immune cell activation requires increased glucose consumption, consequently limiting glucose availability for other cell types like keratinocytes. In psoriasis Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and increases survival under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

The glycolytic activity of Paneth cells provides lactate, which is required by self-renewing intestinal stem cells for oxidative metabolism to activate p38 MAP kinase, ensuring regeneration of a mature crypt.