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Macrophage-Derived MicroRNA-21 Drives Overwhelming Glycolytic and Inflammatory Response during Sepsis via Repression of the PGE 2/IL-10 Axis

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2021

J Immunol. 2021 Aug 1;207(3):902-912. doi: 10.4049/jimmunol.2001251. Epub 2021 Jul 23.

Macrophage-Derived MicroRNA-21 Drives Overwhelming Glycolytic and Inflammatory Response during Sepsis via Repression of the PGE 2/IL-10 Axis

Paulo De Melo, Annie Rocio Pineros Alvarez, Xiang Ye, Amondrea Blackman, Jose Carlos Alves-Filho, Alexandra I Medeiros, Jeffrey Rathmell, Heather Pua, C Henrique Serezani

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. Indiana Biosciences Research Institute, Indianapolis, IN. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil. Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, São Paulo, Brazil. Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN; and. Vanderbilt Institute for Infection, Inflammation, and Immunity, Vanderbilt University Medical Center, Nashville, TN. Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Service type: Knockout mice

Abstract

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-21Δmyel 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-21Δmyel in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21Δmyel mice is dependent on PGE2/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.

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