Sepsis is an
infection-induced severe inflammatory disorder that leads to
multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory
cytokines are culprit for triggering cardiac dysfunction in
sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against
sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with
GW4869, an inhibitor of exosome biogenesis/release, followed by
endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with
GW4869 for 1h prior to
endotoxin treatment or cecal
ligation/
puncture (CLP) surgery. We observed that pre-treatment with
GW4869 significantly impaired release of both exosomes and pro-inflammatory
cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12h after LPS treatment or CLP surgery, WT mice pre-treated with
GW4869 displayed lower amounts of exosomes and pro-inflammatory
cytokines in the serum than control PBS-injected mice. Accordingly,
GW4869 treatment diminished the
sepsis-induced cardiac
inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in
sepsis dampens the
sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.