Chronic stress primes innate immune responses in mice and humans

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk. [Display omitted] •Psychological stress reprograms monocytes to a hyperinflammatory primed phenotype•Stress-mediated priming activates transcriptomic and metabolic pathways in monocytes•Stress-mediated priming alters inflammatory responses in mice and humans Barrett et al. investigate the impact of psychological stress on monocytes. They report that psychological stress remodels the chromatin landscape of monocytes and the myeloid transcriptome, with stress-mediated changes skewing monocytes to a primed-hyperinflammatory phenotype. This study provides mechanistic insight into how psychological stress confers risk to inflammation-based disorders.