Mesenchymal stromal cells induce neutrophil aggregation and extracellular vesicle storms for systemic lupus erythematosus.

Mesenchymal stromal cell (MSC) transplantation has achieved significant clinical benefits for many diseases, such as systemic lupus erythematosus (SLE) and inflammatory diseases. However, the detailed therapeutic mechanism of MSCs is not fully understood. Here, in the SLE treatment, we show that MSC transplantation triggers recipient bone marrow neutrophil aggregation to generate an endogenous extracellular vesicle (EV) storm in the circulation via the TNFα/ICAM-1/Rab11b axis. Interestingly, blockade of the EV storm abolishes the MSC-mediated therapeutic effect for SLE. The level of EV storm is positively associated with the therapeutic effect of MSCs in SLE patients. Mechanistically, aggregated neutrophils-derived EV storms equalize Th17 and T-regulatory (Treg) cells to promote immune tolerance and disease remission via the DHA/LILRB4/STAT5/STAT3 pathway in the MSC treatment for SLE. Taken together, our findings reveal a new immune-modulating function of MSCs through the induction of endogenous neutrophil aggregation in the bone marrow, which results in the secretion of EV storms for immune tolerance in SLE mice and patients. In addition, this study revealed a previously unknown role of the recipient EV storm in determining the therapeutic effect of MSC in SLE, and the recipient EV storm can be used to predict the therapeutic efficacy of MSCs in SLE therapy.