Nature Communications · 2019 · 153 citations · 61 references
Life SciencesImmunologyPathologyAutoimmunityImmunopathologyInflammationCytokine BiologyCytokine SignalingInflammatory Cell ResponsesMacrophage BiologySystemic SclerosisTrained ImmunityFibrosis-associated CytokinesImmune Cell Cytokine ProductionInflammatory Cytokine ProductionMacrophage Cytokine ProductionMacrophage ImmunomodulationMacrophage Inflammatory ResponsesMacrophage-mediated FibrosisTraining Immunity
Chronic inflammation and fibrosis arise from aberrant macrophage activation, and macrophages can acquire memory‑like traits after antigen exposure. The study investigates how BCG or low‑dose LPS stimulation modifies macrophage phenotype, cytokine production, chromatin, and metabolism. Macrophages were stimulated with BCG or low‑dose LPS and assessed for changes in phenotype, cytokine output, chromatin state, and metabolic pathways. Low‑dose LPS training alleviates fibrosis and inflammation in a systemic sclerosis mouse model, whereas BCG training exacerbates disease; adoptive transfer of trained macrophages reproduces these effects, and coculture with low‑dose LPS‑trained macrophages reduces fibroblast activation in mice and patients, indicating that trained immunity could be targeted to treat SSc and other fibrotic disorders.
Abstract 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.
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