Psychological/physical stressors and local tissue damage increase inflammatory proteins in tissues and blood in humans and animals, in the absence of pathogenic disease. Stress-evoked cytokine/chemokine responses or “sterile inflammation”, can facilitate host survival and/or negatively impact health, depending on context. Recent evidence supports the hypothesis that systemic stress-evoked sterile inflammation is initiated by the sympathetic nervous system, resulting in the elevation of exosome-associated immune-stimulatory endogenous danger/damage associated molecular patterns (DAMPs) and a reduction in immune-inhibitory microRNA (miRNA) which are carried in the circulation to tissues throughout the body. We propose that sterile inflammation should be considered an elemental feature of the stress response and that circulating exosomes transporting immune- modulatory signals, may play a role fundamental role in immune homeostasis.