Simultaneous activation of the liver X receptors (LXRα and LXRβ) drives murine collagen-induced arthritis disease pathology

Background It has previously been shown that dual activation of the Liver X Receptors (LXR alpha and LXR beta) by the agonist, GW3965, enhances pathology in a murine model of collagen-induced arthritis. Objective To determine whether LXR alpha or LXR beta have discrete roles in driving articular inflammation. Methods Arthritis was induced in male C57BL/6 wild-type (WT), LXR alpha-/-, LXR beta-/- and LXR alpha/beta double KO mice by injection with type II collagen and treated with 30 mg/kg of the LXR agonist GW3965 or vehicle control. The mice were monitored for articular inflammation and cartilage degradation by scoring for clinical signs of arthritis and by histological examination of the joints. Results Administration of 30 mg/kg GW3965 significantly increases the severity of arthritis in WT but not LXR alpha-/-, LXR beta-/- or LXR alpha/beta KO mice as assessed by an increase in the clinical score, paw thickness and articular histological analysis. Conclusion The proinflammatory effects associated with the administration of GW3965 are mediated specifically through LXRs. The absence of increased disease severity in the LXR alpha-/- and LXR beta-/- GW3965-treated groups shows for the first time that agonism of both LXR alpha and LXR beta is required to drive proinflammatory pathways in vivo.