Abstract

Oxylipins modulate the behavior of immune cells in inflammation. Soluble epoxide hydrolase (sEH) converts anti-inflammatory epoxyeicosatrienoic acid (EET) to dihydroxyeicosatrienoic acid (DHET). An sEH-inhibitor, TPPU, has been demonstrated to ameliorate lipopolysaccharide (LPS)- and sepsis-induced inflammation via EETs. The immunomodulatory role of DHET is not well characterized. We hypothesized that TPPU dampens inflammation and that sEH-derived DHET alters neutrophil functionality in burn induced inflammation. Outbred mice were treated with vehicle, TPPU or 14,15-DHET and immediately subjected to either sham or dorsal scald 28% total body surface area burn injury. After 6 and 24 h, interleukin 6 (IL-6) serum levels and neutrophil activation were analyzed. For in vitro analyses, bone marrow derived neutrophil functionality and mRNA expression were examined. In vivo, 14,15-DHET and IL-6 serum concentrations were decreased after burn injury with TPPU administration. In vitro, 14,15-DHET impaired neutrophil chemotaxis, acidification, CXCR1/CXCR2 expression and reactive oxygen species (ROS) production, the latter independent from p38MAPK and PI3K signaling. We conclude that TPPU administration decreases DHET post-burn. Furthermore, DHET downregulates key neutrophil immune functions and mRNA expression. Altogether, these data reveal that TPPU not only increases anti-inflammatory and inflammation resolving EET levels, but also prevents potential impairment of neutrophils by DHET in trauma.

Highlights

  • The concept that oxylipins can modulate the behavior of immune cells in inflammatory diseases has evolved over the last ­decades[1,2,3]

  • We hypothesized that a beneficial clinical effect can be seen reflected by the decrease of systemic interleukin 6 (IL-6) levels and that the product 14,15-dihydroxyeicosatrienoic acid (DHET) impairs neutrophil functionality

  • These results suggest that the impairment of neutrophil Reactive Oxygen Species (ROS) production by 14,15-DHET is independent from p38MAP kinase and PI3K signaling pathways

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Summary

Introduction

The concept that oxylipins can modulate the behavior of immune cells in inflammatory diseases has evolved over the last ­decades[1,2,3]. Administering sEH reduced the release of pro-inflammatory cytokines in murine ­endotoxemia[10,11], increased survival in a mouse sepsis ­model[12], and reduced neuronal death in an intracerebral hemorrhage ­model[13] Some studies attributed these effects to the anti-inflammatory properties of E­ ETs11,12, which are increased upon inhibition of sEH. Previous studies examining modulation of inflammation by oxylipins focused on the effect on ­macrophages[12,24], the regulation of neutrophil functionality is not yet well characterized Based upon this limited literature, we tested whether TPPU would alter systemic inflammation after burn injury and hypothesized that sEH-derived DHETs alter immune function in neutrophils that play key roles in burn induced inflammation

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