Abstract
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.
Highlights
Low-grade endotoxemia is a risk factor for chronic non-resolving inflammatory diseases
This study reveals novel mechanisms that underlie cell necroptosis and low-grade inflammation preferentially induced by a super-low dose of LPS
This effect may be facilitated by enhanced mitochondrial fission, reduced fusion mediated by reduced dynamin-related protein 1 (Drp1) phosphorylation, and mitofusin 1 (Mfn1) degradation
Summary
Low-grade endotoxemia is a risk factor for chronic non-resolving inflammatory diseases. 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. The mechanisms responsible for the non-resolving, low-grade inflammation initiated by a super-low dose of LPS are not well understood To address this critical question, we examined the effects of a super-low dose of LPS on cellular necroptosis as well as key upstream signaling pathways. We demonstrate that a super-low dose of LPS potently induces necroptosis through an interleukin 1 receptor-associated kinase 1 (IRAK-1)-dependent pathway that leads to selective activation of Drp and degradation of Mfn
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