Liver X Receptor Activation Impairs Neutrophil Functions and Aggravates Sepsis

• Published in: The Journal of infectious diseases Vol. 221; no. 9; pp. 1542 - 1553
• Main Authors: Souto, Fabrício O, Castanheira, Fernanda V S, Trevelin, Silvia C, Lima, Braulio H F, Cebinelli, Guilherme Cesar Martelossi, Turato, Walter M, Auxiliadora-Martins, Maria, Basile-Filho, Anibal, Alves-Filho, Jose Carlos, Cunha, Fernando Q
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 07.04.2020
• Subjects: ABCA1 protein; Adult; Animals; ATP Binding Cassette Transporter 1 - metabolism; ATP-binding protein; Bacteremia; Cecum; Cecum - microbiology; Cecum - surgery; Cell activation; Chemotactic response; Disease Models, Animal; Female; Humans; Inflammation; Inflammatory diseases; Interleukin-8 - metabolism; Leukocytes (neutrophilic); Ligation; Lipid metabolism; Liver X receptors; Liver X Receptors - agonists; Liver X Receptors - metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Multiple Organ Failure - immunology; Multiple Organ Failure - microbiology; Neutrophil Infiltration - immunology; Neutrophils; Neutrophils - metabolism; Neutrophils - pathology; Nuclear receptors; Peritoneum; Punctures; Receptor mechanisms; Sepsis; Sepsis - immunology; Sepsis - metabolism; Sepsis - microbiology; killing; neutrophil migration; inflammation; LXRs; sepsis
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiz635

Abstract Background 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. Methods We used the model of cecal ligation and puncture (CLP) to investigate the role of LXR activation during sepsis. Results 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. Conclusions Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.