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 they maintain 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 PI3Kinase) and reduced chromatin accessibility at mitochondrial respiration 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. RNAseq and ATACseq of isolated bone marrow monoctyes from 6 mice (3 stress, 3 control). RNAseq of isolated bone marrow monocytes stimulated with LPS of 16 pools of 4 mice each (4 pools control unstimulated, 4 pools stressed unstimulated, 4 pools control stimulated, 4 pools stressed stimulated). RNAseq of isolated whole blood monocytes from humans with high and low stress (12 high stress, 15 low stress) from the HARP study.