Macrophage-Derived MicroRNA-21 Drives Overwhelming Glycolytic and Inflammatory Response during Sepsis via Repression of the PGE₂/IL-10 Axis

Myeloid cells are critical for systemic inflammation, microbial control, and organ damage during sepsis. MicroRNAs are small noncoding RNAs that can dictate the outcome of sepsis. The role of myeloid-based expression of microRNA-21 (miR-21) in sepsis is inconclusive. In this study, we show that sepsis enhanced miR-21 expression in both peritoneal macrophages and neutrophils from septic C57BL/6J mice, and the deletion of miR-21 locus in myeloid cells (miR-21(Delta myel) mice) enhanced animal survival, decreased bacterial growth, decreased systemic inflammation, and decreased organ damage. Resistance to sepsis was associated with a reduction of aerobic glycolysis and increased levels of the anti-inflammatory mediators PGE(2) and IL-10 in miR-21(Delta myel) in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21(Delta myel) mice is dependent on PGE(2)/IL-10-mediated inhibition of glycolysis. Together, these findings demonstrate that expression of miR-21 in myeloid cells orchestrates the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm during sepsis.