Mast cells-derived exosomes worsen the development of experimental cerebral malaria.

ABSTRACT

Cerebral malaria (CM) is the most severe neurological complication caused by Plasmodium falciparum infection. The accumulating evidence demonstrated that mast cells (MCs) and its mediators played a critical role in mediating malaria severity. Earlier studies identified that exosomes were emerging as key mediators of intercellular communication and can be released from several kinds of MCs. However, the potential functions and pathological mechanisms of MCs-derived exosomes (MCs-Exo) impacting on CM pathogenesis remain largely unknown. Herein, we utilized an experimental CM (ECM) model (C57BL/6 mice infected with P. berghei ANKA strain), and then intravenously (i.v.) injected MCs-Exo into P. berghei ANKA-infected mice to unfold this mechanism and investigate the effect of MCs-Exo on ECM pathogenies. We also used an in vitro model by investigating the pathogenesis development of brain microvascular endothelial cells line (bEnd.3 cells) co-cultured with P. berghei ANKA blood-stage soluble antigen (PbAg) after MCs-Exo treatment. The higher numbers of MCs and levels of MCs degranulation were observed in skin, cervical lymph node, and brain of ECM mice than those of the uninfected mice. Exosomes were successfully isolated from culture supernatants of mouse MCs line (P815 cells) and characterized by spherical vesicles with the diameter of 30-150 nm, and expression of typical exosomal markers (e.g., CD9, CD63, and CD81). The i.v. injection of MCs-Exo dramatically elevated incidence of ECM in the P. berghei ANKA-infected mice, exacerbated liver and brain histopathological damage, promoted Th1 cytokine response, aggravated brain vascular endothelial activation and blood brain barrier breakdown in ECM mice. In addition, the treatment of MCs-Exo led to the decrease of cells viability and mRNA levels of Ang-1, ZO-1, and Claudin-5, but increase of mRNA levels of Ang-2, CCL2, CXCL1, and CXCL9 in bEnd.3 cells co-cultured with PbAg in vitro. Taken together, our data indicated that MCs-Exo could worsen pathogenesis of ECM in mice.