Molecular and cellular mechanisms responsible for cellular stress and low-grade inflammation induced by super-low dose endotoxin [Signal Transduction]

April 22nd, 2014 by Baker, B., Maitra, U., Geng, S., Li, L.

Super-low dose endotoxemia in experimental animals and humans are linked with low-grade chronic inflammatory diseases. However, the underlying molecular and cellular mechanisms are not well understood. In this study, we examined the effects of super-low dose LPS on low-grade inflammation in macrophages as well as underlying mechanisms. We observed that super-low dose LPS induces mitochondrial fission and cell necroptosis in primary murine macrophages, dependent upon interleukin-1 receptor associated kinase (IRAK-1). Mechanistically, our study reveals that super-low dose LPS causes protein ubiquitination and degradation of mitofusin 1 (Mfn1), a molecule required for maintaining proper mitochondrial fusion. Super-low dose LPS also leads to dephosphorylation and activation of Drp1, a molecule responsible for mitochondrial fission and cell necroptosis. Furthermore, we demonstrated that super-low dose LPS activates receptor interacting protein 3 kinase (RIP3), a key molecule critical for the assembly of necrosome complex, the initiation of Drp1 dephosphorylation and necroptosis. The effects of super-low dose LPS are abolished in macrophages harvested from IRAK-1 deficient mice. Taken together, our study identified a novel molecular pathway that leads to cellular stress and necroptosis in macrophages challenged with super-low dose endotoxin. This may reconcile low-grade inflammation often associated with low-grade endotoxemia.
  • Posted in Journal of Biological Chemistry, Publications
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