Future studies should elucidate the tissue origin of these stress modified exosomes and examine if a1-ADR blockade in stressed animals affects their cytosolic Hsp72 and miR-142-5p, thus indicating whether a1-ADR Bortezomib citations activation is critical for their transcription and synthesis or their exosomal loading. The release of Hsp72 and miRNAs through an exosomal pathway has several advantages. Most notably, exosomes provide a protective lipid bi-layer that can facilitate long distance communication between cells. From a stress physiology perspective, this form of cellular communication may be evolutionarily advantageous. For example, if an organism is subjected to a harmful stressor, such as a predator, the organism’s cells could secrete stress-modified exosomes into the circulation prior to experiencing injury. When injury occurs, stress-modified exosomes are already in the circulation and available to facilitate the host immune response. Cytokine induction by resident leukocytes at the site of injury triggers the activation and expression of adhesion molecules on the adjacent vascular endothelium. Since intercellular adhesion molecules are present on exosomes, plasma exosomes could bind ICAM receptors on vascular endothelial cells and consequently leave the circulation and migrate to the injured tissue. At the site of infection, stressmodified exosomes could boost innate immunity through Hsp72mediated TLR4 activation of macrophages and neutrophils, or transfer their content through clathrin-mediated endocytosis with a recipient cell, subsequently stimulating a pro-inflammatory cytokine response and enhancing the organism’s chance of survival. There are a variety of clinical applications for stress-modified exosomes that could potentially modulate immunity. For example, exposing cells to a non-lethal stressor, such as heat, to elevate Hsp72 and down-regulate miR-142-5p and -203 in exosomes could enhance the immunogenicity of exosome-based vaccines, specifically cancer vaccines. Alternatively, since exosomes are capable of delivering their content to recipient cells, they could transfer their content to target cells, where Hsp72 could translocate to the target cell’s cytosol and perform its cytoprotective and anti-apoptotic functions and miRNAs could modulate mRNA translation. In summary, our data indicate that in vivo exposure to an acute stressor modifies the proteomic and miRNA character of exosomes released into the plasma, likely impacting innate immune function through TLR association, monocyte differentiation, and cytokine secretion. Furthermore, our results suggest that SNS activation of a1-ADRs is a critical component of some of these exosomal modifications. Given the known immunomodulatory and protective functions of Hsp72, miRNA, and exosomes, we speculate that modulation of plasma exosomes is a critical component of the stress response. Future studies should further identify the immunomodulatory factors and cellular sources of stress-modified exosomes in the plasma, which will challenge current paradigms concerning the mechanisms of stress-evoked modulation of immunity and advance knowledge concerning their use in immunotherapy.