Molecular and cellular mechanisms responsible for cellular stress and low-grade inflammation induced by a super-low dose of endotoxin.
Super-low-dose endotoxemia in experimental animals and humans is linked to low-grade chronic inflammatory diseases. However, the underlying molecular and cellular mechanisms are not well understood. In this study, we examined the effects of a super-low dose of LPS on low-grade inflammation in macrophages as well as underlying mechanisms. We observed that a super-low dose of 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 a super-low dose of LPS causes protein ubiquitination and degradation of mitofusin 1 (Mfn1), a molecule required for maintaining proper mitochondrial fusion. A super-low dose of LPS also leads to dephosphorylation and activation of Drp1, a molecule responsible for mitochondrial fission and cell necroptosis. Furthermore, we demonstrated that a super-low dose of LPS activates receptor interacting protein 3 kinase (RIP3), a key molecule critical for the assembly of the necrosome complex, the initiation of Drp1 dephosphorylation, and necroptosis. The effects of a super-low dose of 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 a super-low dose of endotoxin. This may reconcile low-grade inflammation often associated with low-grade endotoxemia.
From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910.
Bianca
B
Baker
From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910.
Urmila
U
Maitra
From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910.
Shuo
S
Geng
From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910 lwli@vt.edu.
Liwu
L
Li
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress
D004731:Endotoxins; D053592:Interleukin-1 Receptor-Associated Kinases; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse
Cellular Immune Response; Chronic Stress; Inflammation; Innate Immunity; Lipopolysaccharide (LPS)