Neutrophils restrain sepsis associated coagulopathy via extracellular vesicles carrying superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis.

Disseminated intravascular coagulation (DIC) is a complication of sepsis currently lacking effective therapeutic options. Excessive inflammatory responses are emerging triggers of coagulopathy during sepsis, but the interplay between the immune system and coagulation are not fully understood. Here we utilize a murine model of intraperitoneal lipopolysaccharide stimulation and show neutrophils in the circulation mitigate the occurrence of DIC, preventing subsequent septic death. We show circulating neutrophils release extracellular vesicles containing mitochondria, which contain superoxide dismutase 2 upon exposure to lipopolysaccharide. Extracellular superoxide dismutase 2 is necessary to induce neutrophils' antithrombotic function by preventing endothelial reactive oxygen species accumulation and alleviating endothelial dysfunction. Intervening endothelial reactive oxygen species accumulation by antioxidants significantly ameliorates disseminated intravascular coagulation improving survival in this murine model of lipopolysaccharide challenge. These findings reveal an interaction between neutrophils and vascular endothelium which critically regulate coagulation in a model of sepsis and may have potential implications for the management of disseminated intravascular coagulation.

Med23 serves as a gatekeeper of the myeloid potential of hematopoietic stem cells.

In response to myeloablative stresses, HSCs are rapidly activated to replenish myeloid progenitors, while maintaining full potential of self-renewal to ensure life-long hematopoiesis. However, the key factors that orchestrate HSC activities during physiological stresses remain largely unknown. Here we report that Med23 controls the myeloid potential of activated HSCs. Ablation of Med23 in hematopoietic system leads to lymphocytopenia. Med23-deficient HSCs undergo myeloid-biased differentiation and lose the self-renewal capacity. Interestingly, Med23-deficient HSCs are much easier to be activated in response to physiological stresses. Mechanistically, Med23 plays essential roles in maintaining stemness genes expression and suppressing myeloid lineage genes expression. Med23 is downregulated in HSCs and Med23 deletion results in better survival under myeloablative stress. Altogether, our findings identify Med23 as a gatekeeper of myeloid potential of HSCs, thus providing unique insights into the relationship among Med23-mediated transcriptional regulations, the myeloid potential of HSCs and HSC activation upon stresses.