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

Abstract

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-1TNF and IL-6).While miR-21-/-macrophages failed to induce aerobic glycolysis and production of proinflammatory 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 miR21myel 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. expression of glycolytic enzymes and transports leads to aerobic glycolysis in macrophages (21,22). Aerobic glycolysis is a critical metabolic pathway required for macrophage activation and proinflammatory activity (23-25). The blockage of glycolysis in macrophages showed a crucial role in the reduction of systemic inflammation leads to improvement of sepsis outcome in experimental models (10,21,26). Exaggerated production of inflammatory mediators and aerobic glycolysis are critical determinants of organ dysfunction during sepsis (27,28).Recent studies have shown that miRNA expression is associated with severe illness and suggested it as potential mediators during sepsis (29). microRNA (miRNAs) are small non-coding RNA molecules (18-to 23-nucleotides) that regulate gene expression by translational repression or posttranscriptional suppression (30,31). miRNAs have an essential role in several biological processes, such as development, differentiation, cell survival, and inflammatory response (32). miRNAs regulate phagocyte cytokine and chemokine response, antimicrobial effector function, pathogen recognition, and tissue repair. The microRNA-21 (miR-21) is highly expressed in different immune cells, such as T/B lymphocytes, monocytes, macrophages, and dendritic cells (33). In vitro studies showed that several inflammatory stimuli as LPS and cytokines as IL-6, TFGβ, and TNF- induce miR21 expression (34,35). Our laboratory showed that miR21 deficiency accounted for the homeostatic...