Erythrocyte-derived Extracellular Vesicles Aggravates Inflammation via Facilitating pro-inflammatory Phenotype of Macrophages

Abstract Transfusion of aged erythrocytes is associated with increased morbidity and mortality in the critically infections with incompletely understood mechanism. Previous studies suggested red blood cell (RBC)-derived extracellular vesicles (EVs) may be potential risk factors for the occurrence of transfusion-related immunomodulation (TRIM). The purpose of our study is to evaluate the effects of EVs under the inflammation condition and explore the underlying mechanisms. In vivo, the activity of EVs was evaluated in the caecal ligation and puncture (CLP)-induced sepsis. Our results showed EVs significantly aggravated the inflammatory response of sepsis in serum and lung tissue by promoting the production of pro-inflammatory factors, TNF-α, IL-6, IL-1β, and reduced the survival rate of septic mice in vivo. Importantly, adoptive transfer EVs pretreated bone marrow-derived macrophages (BMDM) obviously aggravated the systemic pro-inflammatory factors in mice after CLP surgery. In vitro, the pro-inflammatory properties of EVs were shown as elevating the levels of TNF-α, IL-6, IL-1βin LPS-stimulated BMDM. Moreover, EVs promoted the LPS-induced macrophages polarization into pro-inflammatory phenotype. The underlying mechanism was possibly that EVs could up-regulate NF-κB and MAPKs activity to favor macrophage cytokines production.