Editors' ChoiceSepsis

Just keep breathing: How mitochondrial metabolism influences sepsis outcome

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Science Translational Medicine  28 Jan 2015:
Vol. 7, Issue 272, pp. 272ec18
DOI: 10.1126/scitranslmed.aaa5557

Sepsis remains the leading cause of death in the intensive care unit. In patients with sepsis, the body responds to infection with a systemic inflammatory response syndrome (SIRS) that causes intense organ injury and death. Along with tissue injury, intense metabolic changes take place and both glycolytic and lactic pathways are unbalanced.

Whether changes in cell metabolism influence antimicrobial host defense is an intense area of research. It is known that free fatty acids and succinate (a product of glycolysis) influence activation of the inflammasome, a signaling platform required for the production of inflammatory mediators that belong to the interleukin-1 (IL-1) family. Recently, it has been determined that mitochondrial reactive oxygen species production is essential for optimal inflammasome activation. However, whether mitochondrial products derived during SIRS are involved in the pathogenesis of sepsis remains to be determined.

Moon et al. studied the metabolic regulation of inflammatory responses by mitochondrial uncoupling proteins (UCPs), a superfamily of mitochondrial anion carrier proteins during sepsis. Total body and myeloid-specific UCP2-deficient mice were protected from polymicrobial sepsis; this protection correlated with increased UCP2 expression in leukocytes from both septic mice and humans. UCP2-deficient mice displayed reduced lipid synthesis and production of the inflammasome products IL-1β and IL-18 in vivo and in vitro. Pharmacologic and genetic inhibition of fatty acid synthase (FASN) suppressed NLR family, pyrin domain containing 3 (NLRP3)–mediated caspase-1 activation by down-regulation of NLRP3 and IL-1β production. Also, their data suggest that activation of FASN-mediated AKT/ p38 MAPK axis was critical for NLRP3 expression and caspase-1 activation. In conclusion, UCP2 was found to be a propathogenic mediator in sepsis, whereby UCP2 regulates NLRP3-mediated caspase-1 activation through lipid synthesis.

This manuscript opens different therapeutic perspectives regarding the role of UCP2 in controlling different acute and chronic inflammatory human diseases. However, more studies are needed to indicate a possible translational application for UCP2 or NASF in human diseases.

J.-S. Moon et al., UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J. Clin. Invest. 10.1172/JCI78253 (2015). [Full Text]

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