The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

Perucha, Esperanza; Melchiotti, Rossella; Bibby, Jack; Wu, Weiju; Frederiksen, Klaus Stensgaard; Roberts, Ceri A.; Hall, Zoe; LeFriec, Gaelle; Robertson, Kevin A.; Lavender, Paul; Gerwien, Jens; Taams, Leonie S.; Griffin, Julian L.; Rinaldis, Emanuele de; Baarsen, Lisa G. M. van; Kemper, Claudia; Ghazal, Peter; Cope, Andrew P.

doi:10.1038/s41467-019-08332-9

Cited by 107 publications

(85 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, a pathway analysis revealed that the top five canonical pathways upregulated in NCOR1deficient naïve CD4 + T cells displayed an overrepresentation of cholesterol biosynthesis pathways (Supplementary Figure 2B), further supporting the conclusion that NCOR1 regulates cholesterol metabolism in naïve CD4 + T cells. Upon CD4 + T cell activation cholesterol biosynthesis is increased and its metabolites are crucial for Th effector differentiation and function (47)(48)(49). Cholesterol homeostasis gene sets were not enriched in NCOR1-deficient Th1 or Th17 cells, suggesting a specific role for NCOR1 in naïve CD4 + T cells in setting up transcriptional programs required for cholesterol metabolism.…”

Section: Discussionmentioning

confidence: 98%

NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

et al. 2020

View full text Add to dashboard Cite

The differentiation of naïve CD4 + T cells into T helper (Th) subsets is key for a functional immune response and has to be tightly controlled by transcriptional and epigenetic processes. However, the function of cofactors that connect gene-specific transcription factors with repressive chromatin-modifying enzymes in Th cells is yet unknown. Here we demonstrate an essential role for nuclear receptor corepressor 1 (NCOR1) in regulating naïve CD4 + T cell and Th1/Th17 effector transcriptomes. Moreover, NCOR1 binds to a conserved cis-regulatory element within the Ifng locus and controls the extent of IFNγ expression in Th1 cells. Further, NCOR1 controls the survival of activated CD4 + T cells and Th1 cells in vitro, while Th17 cell survival was not affected in the absence of NCOR1. In vivo, effector functions were compromised since adoptive transfer of NCOR1-deficient CD4 + T cells resulted in attenuated colitis due to lower frequencies of IFNγ + and IFNγ + IL-17A + Th cells and overall reduced CD4 + T cell numbers. Collectively, our data demonstrate that the coregulator NCOR1 shapes transcriptional landscapes in CD4 + T cells and controls Th1/Th17 effector functions.

show abstract

Section: Discussionmentioning

confidence: 98%

NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…While de novo FAS has been shown to play an important role in effector CD4 + T cell functions, cholesterol metabolism is involved in the regulation of the anti-inflammatory response in human CD4 + T cells (Perucha et al, 2019). Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ + to IL-10 + showed a specific block in immune resolution, defined as a significant decrease in c-Maf/IL-10 expression (Perucha et al, 2019).…”

Section: Lipid Metabolismmentioning

confidence: 99%

Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

View full text Add to dashboard Cite

Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipocytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.

show abstract

“…IL-10 is an anti-inflammatory and pro-resolving factor that can work to inhibit pro-inflammatory cytokines [22] . Increased IL-4 is associated with allergic airway response; [23] and both IL-4 and IL-10 alter macrophage lipid metabolism [24] . However, in a separate study from our group, IL-4 and IL-10 were not affected by e-cig use in never-smokers, although the study was of brief duration [25] .…”

Section: Discussionmentioning

confidence: 99%

Lipid laden macrophages and electronic cigarettes in healthy adults

et al. 2020

View full text Add to dashboard Cite

Background An outbreak of E-cigarette or Vaping Product Use-Associated Lung Injury (EVALI) with significant morbidity and mortality was reported in 2019. While most patients with EVALI report vaping tetrahydrocannabinol (THC) oils contaminated with vitamin E acetate, a subset report only vaping with nicotine-containing electronic cigarettes (e-cigs). Whether or not e-cigs cause EVALI, the outbreak highlights the need for identifying long term health effects of e-cigs. EVALI pathology includes alveolar damage, pneumonitis and/or organizing pneumonia, often with lipid-laden macrophages (LLM). We assessed LLM in the lungs of healthy smokers, e-cig users, and never-smokers as a potential marker of e-cig toxicity and EVALI. Methods A cross-sectional study using bronchoscopy was conducted in healthy smokers, e-cig users, and never-smokers ( n = 64). LLM, inflammatory cell counts, and cytokines were determined in bronchial alveolar fluids (BAL). E-cig users included both never-smokers and former light smokers. Findings High LLM was found in the lungs of almost all smokers and half of the e-cig users, but not those of never-smokers. LLM were not related to THC exposure or smoking history. LLM were significantly associated with inflammatory cytokines IL-4 and IL-10 in e-cig users, but not smoking-related cytokines. Interpretation This is the first report of lung LLM comparing apparently healthy smokers, e-cig users, and never-smokers. LLM are not a specific marker for EVALI given the frequent positivity in smokers; whether LLMs are a marker of lung inflammation in some e-cig users requires further study. Funding The National Cancer Institute, the National Heart, Lung, and Blood Institute, the Food and Drug Administration Center for Tobacco Products, the National Center For Advancing Translational Sciences, and Pelotonia Intramural Research Funds

show abstract

The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

Cited by 107 publications

References 65 publications

NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

Metabolic Checkpoints in Rheumatoid Arthritis

Lipid laden macrophages and electronic cigarettes in healthy adults

Contact Info

Product

Resources

About