AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury
Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.
We thank Ken Inoki from the University of Michigan for the anti-phospho-Thr479-AMPK antibody. Funding was provided by National Institutes of Health Grant HL107585 to JW Zmijewski.
- 6.Force ADT, et al. (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA. 307:2526–33.Google Scholar
- 61.Labuzek K, Liber S, Gabryel B, Adamczyk J, Okopien B. Metformin increases phagocytosis and acidifies lysosomal/endosomal compartments in AMPK-dependent manner in rat primary microglia. Naunyn Schmiedebergs Arch. Pharmacol. 381:171–86.Google Scholar
- 69.Metformin in Longevity Study (MILES) [Internet]. (2016) [updated 2015 Dec 8; cited 2016 Jan 29]. Available from: https://doi.org/clinicaltrials.gov/ct2/show/record/NCT02432287ClinicalTrials.gov identifier: NCT02432287.