Innate Priming of Neutrophils Potentiates Systemic Multiorgan Injury

Excessive inflammatory reactions mediated by first-responder cells such as neutrophils contribute to the severity of multiorgan failure associated with systemic injury and infection. Systemic subclinical endotoxemia due to mucosal leakage may aggravate neutrophil activation and tissue injury. However, mechanisms responsible for neutrophil inflammatory polarization are not well understood. In this study, we demonstrate that subclinical low-dose endotoxemia can potently polarize neutrophils into an inflammatory state in vivo and in vitro, as reflected in elevated expression of adhesion molecules such as ICAM-1 and CD29, and reduced expression of suppressor molecule CD244. When subjected to a controlled administration of gut-damaging chemical dextran sulfate sodium, mice conditioned with subclinical dose LPS exhibit significantly elevated infiltration of neutrophils into organs such as liver, colon, and spleen, associated with severe multiorgan damage as measured by biochemical as well as histological assays. Subclinical dose LPS is sufficient to induce potent activation of SRC kinase as well as downstream activation of STAT1/STAT5 in neutrophils, contributing to the inflammatory neutrophil polarization. We also demonstrate that the administration of 4-phenylbutyric acid, an agent known to relieve cell stress and enhance peroxisome function, can reduce the activation of SRC kinase and enhance the expression of suppressor molecule CD244 in neutrophils. We show that i.v. injection of 4-phenylbutyric acid conditioned neutrophils can effectively reduce the severity of multiorgan damage in mice challenged with dextran sulfate sodium. Collectively, our data, to our knowledge, reveal novel inflammatory polarization of neutrophils by subclinical endotoxemia conducive for aggravated multiorgan damage as well as potential therapeutic intervention.