Exosomal miR-21 secreted by IL-1β-primed-mesenchymal stem cells induces macrophage M2 polarization and ameliorates sepsis

Sepsis occurs due to a damaging host response to infection and is the chief cause of death in most intensive care units. Mesenchymal stem cells (MSCs) exhibit immunomodulatory properties and can modulate key cells of the innate and adaptive immune systems through various effector mechanisms, such as exosomes. Exosomes and their microRNA (miRNA or miR) cargo including miR-21 can initiate profound phenotypic changes in the tumor microenvironment due to their intercellular communication transmitting the pleiotropic messages between different cell types, tissues, and body fluids. Here, we aimed to characterize the effect of miR-21 delivered from MSC-derived exosomes on the polarization of macrophages in a mouse sepsis model. First, we isolated exosomes from interleukin-1β (IL-1β)-pretreated murine MSCs (βMSCs) and injected them into cecal ligation and puncture (CLP) septic models. We found that βMSCs-derived exosomes could more effectively induce M2-like polarization of macrophages in vitro and in vivo. Administration of βMSCs-derived exosomes attenuated the symptoms in septic mice more effectively and increased their survival rate as compared to exosomes released by naïve MSCs. Importantly, we found that miR-21 was abundantly upregulated in MSCs upon IL-1β stimulation and packaged into exosomes. This exosomal miR-21 was transferred to macrophages, leading to M2 polarization in vitro and in vivo. The therapeutic efficacy of βMSC-derived exosomes was partially lost upon miR-21 inhibition by its specific inhibitors. More specifically, we demonstrated βMSCs-derived exosomes inhibited the effects of PDCD4, the target gene of miR-21, on macrophage polarization and sepsis. In conclusion, exosomal miR-21 emerged as a key mediator of IL-1β pretreatment induced immunomodulatory properties of MSCs. The study indicated a novel basis for therapeutic application of MSCs in sepsis.