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Project description:Autoimmune inflammation triggers an HSC-derived trained immunity program in myeloid cells
| PRJNA888060 | ENA
Project description:Trained immunity occurs when inflammatory stimulation reprograms myeloid cells to have increased effector functions upon secondary stimulation. Interestingly, the secondary stimulation can occur well beyond the lifetime of an individual myeloid cell, thus memory of immune training must reside in the hematopoietic system. After showing that long-term hematopoietic stem cells (HSCLT) from mice treated with pristane for eight weeks generate trained macrophages, we sought to uncover mechanisms underlying the heritable trained immunity program in myeloid cells. To do this we transplanted HSCLT from pristane mice into congenic recipients, and after 18 weeks of engraftment we generated bone marrow derived macrophages (BMDMs) in vitro. We then analyzed the chromatin landscape and transcriptome using low input chromatin accessibility and transcriptomics sequencing (LiCAT-seq) which allows for the co-generation of RNA-seq and ATAC-seq libraries from the same cellular pool. With this approach we found a unique epigenetic phenotype of reduced chromatin accessibility at metabolic genes in BMDMs from pristane HSCLT, which resulted in reduced transcription of metabolic genes, leading to reduced metabolism in BMDMs.
2024-10-15 | GSE267569 | GEO
Project description:Trained immunity occurs when inflammatory stimulation reprograms myeloid cells to have increased effector functions upon secondary stimulation. We found that autoimmune inflammation indiced trained immunity in bone marrow derived macrophages (BMDMs) in mice treated with pristane for eight weeks. We then analyzed the chromatin landscape and transcriptome using low input chromatin accessibility and transcriptomics sequencing (LiCAT-seq) which allows for the co-generation of RNA-seq and ATAC-seq libraries from the same cellular pool. With this approach we found that BMDMs had increased chromatin accessibility at metabolic genes and inflammatory related genes in BMDMs from pristane treated mice, which resulted in increased transcription of metabolic and inflammatory genes, leading to enhanced metabolism and inflammatory functions in BMDMs.
2024-10-15 | GSE267563 | GEO
Project description:Trained immunity occurs when inflammatory stimulation reprograms myeloid cells to have increased effector functions upon secondary stimulation. Interestingly, the secondary stimulation can occur well beyond the lifetime of an individual myeloid cell, thus memory of immune training must reside in the hematopoietic system. After showing that long-term hematopoietic stem cells (HSCLT) from mice treated with pristane for eight weeks generate trained macrophages, we sought to uncover mechanisms underlying the heritable trained immunity program in myeloid cells. To do this we transplanted HSCLT from pristane mice into congenic recipients, and after 18 weeks of engraftment we generated bone marrow derived macrophages (BMDMs) in vitro. We then analyzed the chromatin landscape and transcriptome using low input chromatin accessibility and transcriptomics sequencing (LiCAT-seq) which allows for the co-generation of RNA-seq and ATAC-seq libraries from the same cellular pool. With this approach we found a unique epigenetic phenotype of reduced chromatin accessibility at metabolic genes in BMDMs from pristane HSCLT, which resulted in reduced transcription of metabolic genes, leading to reduced metabolism in BMDMs.
2024-10-15 | GSE267518 | GEO
Project description:Trained immunity occurs when inflammatory stimulation reprograms myeloid cells to have increased effector functions upon secondary stimulation. We found that autoimmune inflammation indiced trained immunity in bone marrow derived macrophages (BMDMs) in mice treated with pristane for eight weeks. We then analyzed the chromatin landscape and transcriptome using low input chromatin accessibility and transcriptomics sequencing (LiCAT-seq) which allows for the co-generation of RNA-seq and ATAC-seq libraries from the same cellular pool. With this approach we found that BMDMs had increased chromatin accessibility at metabolic genes and inflammatory related genes in BMDMs from pristane treated mice, which resulted in increased transcription of metabolic and inflammatory genes, leading to enhanced metabolism and inflammatory functions in BMDMs.
2024-10-15 | GSE267516 | GEO
Project description:Chronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.
| S-EPMC6906311 | biostudies-literature
Project description:IntroductionTrained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations.Materials and methodsWe extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production.ResultsMonocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels.DiscussionOverall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort.
| S-EPMC10701735 | biostudies-literature
Project description:Trained innate immunity has recently emerged as a novel concept of innate immune cells, such as myeloid cells, exhibiting immune memory, and nonspecific heterologous immunity to protect against infections. The memory and specificity are mediated by epigenetic, metabolic, and functional reprogramming of the myeloid cells and myeloid progenitors (and/or NK cells) in the bone marrow and peripheral tissues such as gut and lung mucosa. A variety of agents, such as BCG, viruses, and their components, as well as TLR agonists, and cytokines have been shown to be involved in the induction of trained immunity. Since these agents have been widely used in AIDS vaccine development as antigen delivery vectors or adjuvants, myeloid cell mediated trained immunity might also play an important role in protecting against mucosal AIDS virus transmission or in control of virus replication in the major gut mucosal reservoir. Here we review the trained innate immunity induced by these vectors/adjuvants that have been used in AIDS vaccine studies and discuss their role in mucosal vaccine efficacy and possible utilization in AIDS vaccine development. Delineating the protective effect of the trained innate immunity mediated by myeloid cells will guide the design of novel AIDS vaccines.
| S-EPMC7058986 | biostudies-literature
Project description:The mammalian target of rapamycin (mTOR) is a signaling molecule that senses environmental cues, such as nutrient status and oxygen supply, to regulate cell growth, proliferation, and other functions. Unchecked, sustained mTOR activity results in defects in HSC function. Inflammatory conditions, such as autoimmune disease, are often associated with defective hematopoiesis. Here, we investigated whether hyperactivation of mTOR in HSCs contributes to hematopoietic defects in autoimmunity and inflammation. We found that in mice deficient in Foxp3 (scurfy mice), a model of autoimmunity, the development of autoimmune disease correlated with progressive bone marrow loss and impaired regenerative capacity of HSCs in competitive bone marrow transplantation. Similarly, LPS-mediated inflammation in C57BL/6 mice led to massive bone marrow cell death and impaired HSC function. Importantly, treatment with rapamycin in both models corrected bone marrow hypocellularity and partially restored hematopoietic activity. In cultured mouse bone marrow cells, treatment with either of the inflammatory cytokines IL-6 or TNF-α was sufficient to activate mTOR, while preventing mTOR activation in vivo required simultaneous inhibition of CCL2, IL-6, and TNF-α. These data strongly suggest that mTOR activation in HSCs by inflammatory cytokines underlies defective hematopoiesis in autoimmune disease and inflammation.
| S-EPMC2964994 | biostudies-literature
Project description:Pre-operative exercise therapy improves outcomes for many patients who undergo surgery. Despite the well-known effects on tolerance to systemic perturbation, the mechanisms by which pre-operative exercise protects the organ that is operated on from inflammatory injury are unclear. Here, we show that four-week aerobic pre-operative exercise significantly attenuates liver injury and inflammation from ischaemia and reperfusion in mice. Remarkably, these beneficial effects last for seven more days after completing pre-operative exercising. We find that exercise specifically drives Kupffer cells toward an anti-inflammatory phenotype with trained immunity via metabolic reprogramming. Mechanistically, exercise-induced HMGB1 release enhances itaconate metabolism in the tricarboxylic acid cycle that impacts Kupffer cells in an NRF2-dependent manner. Therefore, these metabolites and cellular/molecular targets can be investigated as potential exercise-mimicking pharmaceutical candidates to protect against liver injury during surgery.
| S-EPMC8462058 | biostudies-literature