ER-to-lysosome Ca2+refilling followed by K+efflux-coupled store-operated Ca2+entry in inflammasome activation and metabolic inflammation

Abstract

AbstractWe studied lysosomal Ca2+in inflammasome. LPS+palmitic acid (PA) decreased lysosomal Ca2+([Ca2+]Lys) and increased [Ca2+]ithrough mitochondrial ROS, which was suppressed inTrpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated byTrpm2KO. ER→lysosome Ca2+refilling occurred after lysosomal Ca2+release whose blockade attenuated LPS+PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+efflux whose inhibition reduced ER Ca2+content ([Ca2+]ER) and impaired [Ca2+]Lysrecovery. LPS+PA activated KCa3.1 channel, a Ca2+-activated K+channel. Inhibitors of KCa3.1 channel orKcnn4KO reduced [Ca2+]ER, attenuated increase of [Ca2+]ior inflammasome activation by LPS+PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+release sustained by ER→lysosome Ca2+refilling and K+efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.