title: Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality.
abstract: Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstratedin vitrowith endotoxin priming and tolerance in cultured monocytes. However, previousin vivostudies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre-conditionings with super-low or low dose endotoxin lipopolysaccharide (LPS) cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP). This is in opposite to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET) in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a novel mechanism potentially responsible for the dynamic programming of innate immunityin vivoas it relates to sepsis risks.
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Na
authors.initials: N
authors.lastname: Diao
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Upchurch
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
keywords: Innate immunity; neutrophil; polymicrobial sepsis; pre-conditioning dynamics; super-low dose endotoxin