AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Abstract

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.

Regulation of immunity and inflammation by hypoxia in immunological niches

“…The activity of 5 -AMP-activated protein kinase (AMPK) may be central to these mechanisms, as it was recently shown that administration of an AMPK activator (metformin) could protect mice in a model of sepsis-induced lung injury. This protection was thought to be mediated by a mechanism that includes decreased neutrophil accumulation, attenuated HIF1 signalling and decreased epithelial permeability in the lung 114 .…”

Macrophage-epithelial interactions in pulmonary alveoli

“…Alveolar epithelial AMPK can be activated, for example by high CO2 levels[57]. In a bacterial model of ALI, AMPK activation in the lung was shown to be immunosuppressive, hence protective against ALI[59]. Hence, the extent to which the Ca 2+ -CAM → CAMKKβ → AMPK activation cascade promotes lung repair in ALI requires further consideration.…”

Mitochondrial Dysfunction and Immune Cell Metabolism in Sepsis

“…However, recovery of metabolic activity and organ function is possible, and were strongly regulated by expression of markers of mitochondrial biogenesis such as PRARgamma-coactivator-1a (PGC-1a), nuclear respiratory factors 1 and 2 (NRF-1 and -2), and via repression of the biogenesis suppressor nuclear receptor interacting protein-140 (RIP140) [37464748]. Moreover, most recent pre-clinical studies, and our results, indicated that not only preservation, but also mitochondrial biogenesis is an essential step in reestablishing immune or tissue organ homeostasis during recovery from sepsis [495051]. …”

“…In particular, dissipation of mitochondrial membrane potential, a situation found upon exposure to bacterial product LPS, nearly completely diminished neutrophils chemotaxis [5070]. This is relevant issue because host-generated inflammatory mediators and bacterial products are present in circulation of individuals with established sepsis.…”