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Fructose specifically exacerbates pathogenic-Th17 cell differentiation and autoimmune diseases through ROS-EGFR signal

ABSTRACT: Th17 cells are quite heterogeneous, with pathogenic roles in autoimmunity and non-pathogenic roles in maintaining tissue homeostasis. Although efforts have been made to study genetic and cellular factors in regulating Th17 cell differentiation, little is known about the role of environmental factors and their underlying mechanisms. Here, we revealed that high-fructose intake selectively enhanced the differentiation and function of IL1b+IL-6+IL-23-induced pathogenic Th17 cells (pTh17), without affecting TGFb1+IL-6-induced non-pTh17 cells, and exacerbated autoimmune diseases models. Notably, fructose enhanced both aerobic glycolysis and OXPHOS activity in pTh17 cells, leading to increased ROS production and subsequently promoting their differentiation. N-acetyl cysteine (NAC), a ROS scavenger, specifically impaired pTh17 cell immunity and mitigated autoimmune disease under high-fructose consumption. Mechanistically, ROS accumulation resulted in higher EGFR expression and activation, which subsequently translocated in nucleus to bind with STAT3, enhancing its transcriptional activity of CNS6 and CNS9 regions of Rorc. Taking together, we illustrated a previously unrecognized mechanism underlying the adverse effects of high-fructose intake in pTh17 cell-related pathologies and diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE285450 | GEO | 2025/09/29

REPOSITORIES: GEO

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Fructose specifically exacerbates pathogenic-Th17 cell differentiation and autoimmune diseases through ROS-EGFR signal

Project description:Fructose specifically exacerbates pathogenic-Th17 cell differentiation and autoimmune diseases through ROS-EGFR signal

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Project description:The proportion of pathogenic Th17 (pTh17) cells were significantly higher in RA than that in control individuals and showed a potential relevance with YY1 expression. Increased YY1 expression was observed in pTh17, and the pTh17 differentiation was hampered by YY1 knockdown. We used microarrays to detail the gene expression changes of pTh17 transfected with YY1 shRNA lentivirus and tried to elucidate the potential mechanisms how YY1 can affect pTh17 cell differentiation in RA.

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Induction of pathogenic Th17 cells by salt inducible kinase SGK-1 (NaCl)

Project description:Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions2. Previous studies have shown that IL-23 signaling reinforces the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R)3. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), as an essential node downstream of IL-23 signaling, critical for regulating IL-23R expression and for stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. A serine-threonine kinase homologous to AKT4, SGK1 has been associated with cell cycle and apoptosis, and has been shown to govern Na+ transport and homeostasis5, 6 7, 8. We here show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is a critical regulator for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation. Effects of NaCl on Th17 differentiation

2013-03-07 | E-GEOD-43957 | biostudies-arrayexpress

Induction of pathogenic Th17 cells by salt inducible kinase SGK-1 (SGK-1 KO)

2013-03-07 | E-GEOD-43956 | biostudies-arrayexpress

Stress-Induced Glucocorticoids Exacerbate Inflammation and Autoimmunity by Promoting the Differentiation and Function of Th17 Cells [ChIP-seq]

Project description:Stress elicits inflammatory and autoimmune diseases while concurrently triggering the production of glucocorticoids (GCs), renowned for their anti-inflammatory effects. In addition, IL-17-producing helper T (Th17) cells are pivotal in initiating inflammation and certain autoimmune disorders. However, whether stress-induced GCs exacerbate inflammatory and autoimmune diseases through Th17 cells remains elusive. Here, we show that GCs facilitate the differentiation and survival of Th17 cells in mice. GCs inhibit the expression of TCF1, a negative regulator of Th17 cell differentiation, thereby increasing pathogenic TCF1low Th17 cells characterized by high glycolytic activity. Remarkably, mice lacking the glucocorticoid receptor (GR), specifically in  T cells, manifest less severe experimental autoimmune encephalomyelitis (EAE) and inflammatory colitis. Moreover, stress-induced GCs augment the population of Th17 cells, intensify their IL-17 production, and provoke neutrophil recruitment, resulting in severe inflammation and substantial weight loss in the colitis model. This study demonstrates that stress-induced GCs exacerbate inflammation and autoimmunity by fostering Th17 cell differentiation.

2025-07-31 | GSE235250 | GEO

Stress-Induced Glucocorticoids Exacerbate Inflammation and Autoimmunity by Promoting the Differentiation and Function of Th17 Cells [hTh17_RNAseq]

2025-07-31 | GSE235249 | GEO

Stress-Induced Glucocorticoids Exacerbate Inflammation and Autoimmunity by Promoting the Differentiation and Function of Th17 Cells [mTh17_RNAseq]

2025-07-31 | GSE235248 | GEO

Tripartite motif-containing 33 (Trim33) determines the pathogenic function of Th17 cells

Project description:We report that Tripartite motif-containing 33 (Trim33), a protein that was previously associated with TGF-beta signaling, determines the pathogenic function of Th17 cells. Trim33 deficiency in T cells resulted in resistance to an autoimmune disease model. Lack of Trim33 did not impact TGF-beta signaling in mediating Foxp3 gene expression but greatly reduced TGF-beta induction of IL-17 production during Th17 cell differentiation. Importantly, we found TGF-beta not only increased IL-17 but also suppressed IL-10 expression; absence of Trim33 or Smad2 but not Smad4 in T cells enhanced IL-10 expression. In a Smad2-dependent manner, Trim33 was recruited to Il17 and Il10 gene loci and was crucial in appropriate histone modification accompanying Th17 differentiation. Our study thus demonstrates that Trim33, a non-canonical branch of TGF-beta signaling, programs the pro-inflammatory function of Th17 differentiation by promoting IL-17 and suppressing IL-10 expression. As a critical switch of pathogenic versus regulatory phenotype of T cells, Trim33 may be targeted in treating human autoimmune diseases.

2018-05-02 | GSE113925 | GEO

Regulation of pathogenic T helper 17 cell differentiation by steroid receptor coactivator-3

Project description:T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORgt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here we show that the steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarrays were used to showed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORtdependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical in RORt-dependent gene expression during Th17 cell-driven autoimmune diseases.

2018-05-02 | GSE113927 | GEO

Population transcriptional profiling of Th17 cells, isolated from the lamina propria of the large intestine from 3-6 month old IL-17GFP KI mice

Project description:Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or polarized in vitro under either pathogenic or non-pathogenic differentiation conditions. Computational analysis reveals a spectrum of cellular states in vivo, including a self-renewal state, Th1-like effector/memory states and a dysfunctional/senescent state. Relating these states to in vitro differentiated Th17 cells, unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four novel genes: Gpr65, Plzp, Toso and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity, and can identify targets for selective suppression of pathogenic Th17 cells while sparing non-pathogenic tissue-protective ones. Population transcriptional profiling of Th17 cells, isolated from the lamina propria of the large intestine from 3-6 month old IL-17GFP KI mice

2015-11-20 | E-GEOD-75106 | biostudies-arrayexpress

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