Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors [RNA-seq]

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis- associated immunoparalysis. Training, priming and tolerance regulate similar 'signature' inflammatory genes such as TNF, IL6 and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating Jak-STAT signaling and interferon- stimulated genes, also play a key role regulating training, priming and tolerance via chromatin- mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-g-mediated priming, changes AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a 'training-priming continuum' model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1. Overall design: To investigate priming effect of IFNg on human monocytes vs macrophages, we purified CD14+ monocytes from human buffy coats. Monocytes were cultured overnight at 37°C, 5% CO2 in RPMI-1640 medium supplemented with 10% heat-inactivated defined FBS, penicillin-streptomycin, L-glutamine and 20 ng/ml human M-CSF and treated with indicated stimulation. Macrophages were cultured similary but for 3 days and stimulated with indicated stimulation.