Age-dependent therapeutic effects of liver X receptor-alpha activation in murine polymicrobial sepsis

作者：Botez Gabriela; Piraino Giovanna; Hake Paul W; Ledford John R; O'Connor Michael; Cook James A; Zingarelli Basilia^*

来源：Innate Immunity, 2015, 21(6): 609-618.

DOI：10.1177/1753425915569367

• Liver X receptor-alpha
• T0901317
• sepsis
• lung injury
• NF-kappa B
• age
• neutrophil infiltration

The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor- (LXR) is a regulator of lipid metabolism with associated anti-inflammatory properties. Here, we investigated the role of LXR in age-dependent lung injury and outcome of sepsis. Male C57BL/6, LXR-deficient (LXR-/-) and wild type (WT) (LXR+/+) mice of different ages were subjected to sepsis by cecal ligation and puncture (CLP). In pharmacological studies, treatment with the LXR ligand T0901317 reduced lung neutrophil infiltration in C57BL/6 mice aged from 1 to 8mo when compared with vehicle-treated animals subjected to CLP. The LXR ligand improved survival in young mice (2-3mo old) but did not affect survival or neutrophil infiltration in mature adult mice (11-13mo old). Immunoblotting revealed an age-dependent decrease of lung LXR levels. Young LXR-/- mice (2-3mo old) exhibited earlier mortality than age-matched WT mice after CLP. Lung damage and neutrophil infiltration, lung activation of the pro-inflammatory NF-B and plasma IL-6 levels were higher in LXR-/- mice 18h after CLP compared with LXR+/+ mice. This study suggests that the anti-inflammatory properties of LXR in sepsis are age-dependent and severely compromised in mature adult animals.

• 出版日期2015-8