Hsp70-containing exosomes - potent stimulators of the innate immune system (50.19)

Abstract

AbstractDepending on their intra- and/or extracellular localization heat shock proteins (HSP) either mediate protection against stress-induced cell damage or act as danger signals stimulating the adaptive and innate immune system (1–3). However, it remained elusive how cytosolic HSPs become externalized and thus communicate with immunocompetent effector cells. Several groups demonstrated that a variety of different cell types, including tumor cells, have the capacity for an active release of Hsp70 in detergent-soluble vesicles (4,5). Biophysical properties including floating properties (1.17g/ml) correlating with a maximum acetylcholine esterase activity characterized them as exosomes (3–5). Profiling of luminal proteins revealed that tumor-derived exosomes contain cytosolic proteins but lack ER-residing proteins. An exosomal enrichment of the small GTPase Rab-4 documented their intracellular transport route from the early endosomal compartment to the plasma membrane. Exosomes originating from Hsp70 plasma membrane-positive tumors present Hsp70 on their exosomal membrane. In line with these findings only Hsp70 surface-positive exosomes but not their negative counterparts had the capacity to stimulate the innate immune system (3). These data provide an explanation how the innate immune system might become activated by tumor-derived exosomal Hsp70 in vivo.