Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice

Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-113 to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-113 during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-113 generation. Mechanistically, the knockdown of VDR increased IL-113 generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-113 production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-113, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-113, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the antiinflammatory treatment of cholestatic liver disease. (Am J Pathol 2024, 194: 369-383; https:// doi.org/10.1016/j.ajpath.2023.11.016)