Molecular mechanisms responsible for low-grade cellular stress induced by super low dose lipopolysaccharide (INM2P.421)

Abstract

Abstract Underlying many chronic inflammatory diseases is the persistence of low-grade inflammation. Low doses of lipopolysaccharide are capable of skewing the immune system towards a pro-inflammatory state without inducing anti-inflammatory compensation. While the cumulative effects of this low-grade endotoxemia can be detrimental, the mechanism is poorly understood. Dysregulation of mitochondrial dynamics has been linked to a variety of diseases and disorders including Parkinson’s and Alzheimer’s. We hypothesized that low-dose LPS induces mitochondrial dysregulation by altering mitochondrial dynamics through an IL-1R-associated kinase-1 and Toll-interacting protein dependent mechanism. To test this hypothesis, we utilized western blotting, immunoprecipation, and confocal microscopy techniques in wild-type and knockout bone marrow derived macrophages. In this study, we demonstrate that subclinical low-dose LPS induces mitochondrial fission while suppressing mitochondrial fusion through IRAK -1 and Tollip. Low-dose LPS causes a decrease in Drp1 phosphorylation while increasing total Drp1 protein levels thus, promoting mitochondrial fission in the wild-type cells. In addition, low-dose LPS inhibits Mfn1 levels further inducing mitochondrial fission. Our data reveals a novel role for low-dose LPS in mitochondrial dynamics, which may contribute to skewed and persistent low-grade inflammation and disease progression.