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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\u0394myel 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 PGE2 and IL-10 in miR-21\u0394myel in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21\u0394myel mice is dependent on PGE2\/IL-10\u2013mediated 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.<\/jats:p>","DOI":"10.4049\/jimmunol.2001251","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T15:10:15Z","timestamp":1627053015000},"page":"902-912","source":"Crossref","is-referenced-by-count":26,"title":["Macrophage-Derived MicroRNA-21 Drives Overwhelming Glycolytic and Inflammatory Response during Sepsis via Repression of the PGE2\/IL-10 Axis"],"prefix":"10.1093","volume":"207","author":[{"given":"Paulo","family":"De Melo","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0135-7549","authenticated-orcid":false,"given":"Annie 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