Glucocorticoid resistance and β2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: A systematic review across species

• Chronic stress associates with upregulation in pro-inflammatory gene transcription. • Upregulated gene transcription is specific to peripheral monocytic lineage cells. • Consistent evidence implicates downregulation in GR sensitivity and transcription. • Initial evidence implicates an a-typical β-AR intracellular signaling pathway. • Findings were similar across murine, primate, and human social stressors. Activation of the HPA-axis and SNS are widely accepted to link chronic stress with elevated levels of peripheral pro-inflammatory markers in blood. Yet, empirical evidence showing that peripheral levels of glucocorticoids and/or catecholamines mediate this effect is equivocal. Recent attention has turned to the possibility that cellular sensitivity to these ligands may contribute to inflammatory mediators that accompany chronic stress. We review current evidence for the association of chronic stress with glucocorticoid receptor (GR) and β-adrenergic receptor (β-AR) signaling sensitivity. Across 15 mouse, 7 primate, and 19 human studies, we found that chronic stress reliably associates with downregulation in cellular GR sensitivity, alterations in intracellular β-AR signaling, and upregulation in pro-inflammatory biomarkers in peripheral blood. We also present evidence that alterations in GR and β-AR signaling may be specific to myeloid progenitor cells such that stress-related signaling promotes release of cells that are inherently less sensitive to glucocorticoids and differentially sensitive to catecholamines. Our findings have broad implications for understanding mechanisms by which chronic stress may contribute to pro-inflammatory phenotypes.