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

Innate immunity

PubMedID: 25956304

Botez G, Piraino G, Hake PW, Ledford JR, O'Connor M, Cook JA, Zingarelli B. Age-dependent therapeutic effects of liver X receptor-a activation in murine polymicrobial sepsis. Innate Immun. 2015;.
The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor-a (LXRa) is a regulator of lipid metabolism with associated anti-inflammatory properties. Here, we investigated the role of LXRa in age-dependent lung injury and outcome of sepsis. Male C57BL/6, LXRa-deficient (LXRa(-/-)) and wild type (WT) (LXRa(+/+)) mice of different ages were subjected to sepsis by cecal ligation and puncture (CLP). In pharmacological studies, treatment with the LXRa ligand T0901317 reduced lung neutrophil infiltration in C57BL/6 mice aged from 1 to 8?mo when compared with vehicle-treated animals subjected to CLP. The LXRa ligand improved survival in young mice (2-3?mo old) but did not affect survival or neutrophil infiltration in mature adult mice (11-13?mo old). Immunoblotting revealed an age-dependent decrease of lung LXRa levels. Young LXRa(-/-) mice (2-3?mo 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 LXRa(-/-) mice 18?h after CLP compared with LXRa(+/+) mice. This study suggests that the anti-inflammatory properties of LXRa in sepsis are age-dependent and severely compromised in mature adult animals.