Molecular Mechanisms Responsible for the Selective and Low-grade Induction of Pro-inflammatory mediators by Lipopolysaccharide

Low dose endotoxemia is prevalent in humans with adverse health conditions, and correlates with the pathogenesis of chronic inflammatory diseases such as atherosclerosis, diabetes, and neurological inflammation.  However, the underlying molecular mechanisms are poorly understood.  Here, we demonstrated that subclinical low dose lipopolysaccharide (LPS) skews macrophages into a mild pro-inflammatory state, through cell surface toll-like-receptor 4 (TLR4), interleukin-1 receptor associated kinase-1 (IRAK-1), and toll-interacting-protein (Tollip). Unlike high dose LPS, low dose LPS does not induce robust activation of nuclear factor kappa-B (NFκB), mitogen-activated protein kinases (MAPK) or anti-inflammatory mediators.   Instead, low dose LPS induces activating transcription factor 2 (ATF2) through Tollip-mediated generation of mitochondrial reactive oxygen species (ROS), allowing mild induction of pro-inflammatory mediators. Recently, mitochondrial dysfunction has been implicated in a variety of diseases such as autism, Parkinson’s, and even aging. Researchers are beginning to realize that in addition to studying anatomy to solve these complex problems, we must also look at energy, thus the mitochondria. Our data reveal novel mechanisms responsible for skewed and persistent low grade inflammation, a cardinal feature of chronic inflammatory diseases, which utilizes the mitochondria.