Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Brazil.
J Infect Dis. 2020 Apr 7;221(9):1542-1553. doi: 10.1093/infdis/jiz635.
Liver X receptors (LXRs) are nuclear receptors activated by oxidized lipids and were previously implicated in several metabolic development and inflammatory disorders. Although neutrophils express both LXR-α and LXR-β, the consequences of their activation, particularly during sepsis, remain unknown.
We used the model of cecal ligation and puncture (CLP) to investigate the role of LXR activation during sepsis.
In this study, we verified that LXR activation reduces neutrophil chemotactic and killing abilities in vitro. Mice treated with LXR agonists showed higher sepsis-induced mortality, which could be associated with reduced neutrophil infiltration at the infectious foci, increased bacteremia, systemic inflammatory response, and multiorgan failure. In contrast, septic mice treated with LXR antagonist showed increased number of neutrophils in the peritoneal cavity, reduced bacterial load, and multiorgan dysfunction. More important, neutrophils from septic patients showed increased ABCA1 messenger ribonucleic acid levels (a marker of LXR activation) and impaired chemotactic response toward CXCL8 compared with cells from healthy individuals.
Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.
肝 X 受体（LXRs）是被氧化脂质激活的核受体，先前与多种代谢发育和炎症紊乱有关。尽管中性粒细胞表达 LXR-α 和 LXR-β，但它们的激活后果，特别是在脓毒症期间，仍然未知。
我们使用盲肠结扎和穿刺（CLP）模型来研究 LXR 激活在脓毒症中的作用。
在这项研究中，我们验证了 LXR 激活可降低中性粒细胞体外趋化和杀伤能力。用 LXR 激动剂治疗的小鼠表现出更高的脓毒症诱导死亡率，这可能与感染灶中性粒细胞浸润减少、菌血症增加、全身炎症反应和多器官衰竭有关。相比之下，用 LXR 拮抗剂治疗的脓毒症小鼠在腹腔中表现出更多的中性粒细胞，减少了细菌负荷和多器官功能障碍。更重要的是，与健康个体的细胞相比，脓毒症患者的中性粒细胞中 ABCA1 信使核糖核酸水平（LXR 激活的标志物）升高，并且对 CXCL8 的趋化反应受损。
因此，我们的发现表明 LXR 激活会损害中性粒细胞的功能，这可能导致脓毒症预后不良。
