Macrophage-derived miR-21 drives overwhelming glycolytic and inflammatory response during sepsis via repression of the PGE2/IL-10 axis

Myeloid cells play a critical role in the development of systemic inflammation and organ damage during sepsis. The mechanisms the development of aberrant inflammatory response remains to be elucidated. MicroRNAs are small non-coding RNAs that could prevent the expression of inflammatory molecules. Although the microRNA-21 (miR-21) is abundantly expressed in macrophages, the role of miR-21 in sepsis is controversial. Here we showed that miR-21 is upregulated in neutrophils and macrophages from septic mice. We found that myeloid-specific miR-21 deletion enhances animal survival, followed by decreased bacterial growth and organ damage during sepsis. Increased resistance against sepsis was associated with a reduction of aerobic glycolysis (as determined by reduced extracellular acidification rate (ECAR) and expression of glycolytic enzymes) and systemic inflammatory response (IL-1βTNFα and IL-6). While miR-21-/- macrophages failed to induce aerobic glycolysis and production of pro-inflammatory cytokines, we observed increased levels of the anti-inflammatory mediators’ prostaglandin E2 (PGE2) and IL10. Using blocking antibodies and pharmacological tools, we further discovered that increased survival and decreased systemic inflammation in miR21Δmyel during sepsis is dependent on the PGE2/IL10-mediated glycolysis inhibition. Together, we are showing a heretofore unknown role of macrophage miR21 in the orchestrating the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm and tissue damage during sepsis. ### Competing Interest Statement The authors have declared no competing interest.