The mechanism of Hsp72 release into the circulation during stressor exposure is unclear, but several studies have demonstrated that Hsp72 can associate with exosomes in cell culture and amniotic fluid. Thus far, it is unknown whether stress-induced Hsp72 circulating in the plasma is associated with exosomes. Given the reported immunological properties of both exosomes and extracellular Hsp72, it is important to determine if stressor exposure modifies host Selumetinib clinical trial immunity by increasing Hsp72 associated with plasma exosomes. Exosomes also contain non-coding RNA known as microRNA . Exosomal miRNA can elicit activity on distal cells upon inclusion, regulating target genes and modulating translation of messenger RNA. Various environmental stressors, such as heat and oxidative stress, can modify miRNA associated with TLR mediated inflammation, proinflammatory cytokine expression, and macrophage differentiation, making miRNA another target of interest in stressmodified immunity. To explore the impact of acute stress on plasma exosome miRNA, we analyzed miR-142-5p, -150, -155, and -203 based on evidence of their differential presence in heat stressed rats, involvement in TLR-mediated immunity, and association with macrophage differentiation. We hypothesized that acute stressor exposure modulates the protein and miRNA character of circulating plasma exosomes. Our findings demonstrate that stress modifies plasma exosomes through up-regulation of surface Hsp72 and down-regulation of two miRNAs. Pathway enrichment analysis of the stress-modified exosomal miRNAs target genes reveals functionally enriched pathways implicated in the stress response. Further, we identify sympathetic nervous system activation of the a1-adrenergic receptor as an important signaling process to exosomal elevations of Hsp72 and down-regulation of miR-142-5p. These are the first studies to demonstrate that activation of the stress response modifies plasma exosomes that may be capable of regulating immunity. A variety of disease states can change both the composition and function of exosomes. What remains less clear is if exosomal modifications occur during the acute stress response. In this series of experiments, we reveal that exposure to an intense and acute stressor in the absence of injury or disease alters the proteomic and miRNA composition of plasma exosomes. Additionally, this stressinduced modification of plasma exosomes is partially mediated by SNS activation of a1-ADRs. Circulating Hsp72 is increased following exposure to a variety of acute stressors and the release of the protein may contribute to stress-modulated immunity through activation of macrophages, dendritic cells, and neutrophils, inducing the secretion of pro-inflammatory cytokines. Here we provide evidence that a significant portion of stress-induced Hsp72 is released into the blood via an exosome release pathway. CD63 immunoprecipitation of plasma from stressed rats prior to exosome isolation corresponds to a marked decrease in Hsp72, further supporting its association with circulating exosomes. Analysis of Hsp72 in the exosome enriched fractions following lysing revealed that while Hsp72 is present within the exosome lumen.