P2X7 receptor‐mediated Nlrp3‐inflammasome activation is a genetic determinant of macrophage‐dependent crescentic glomerulonephritis

[摘要] P2RX7,amediatorofIL‐1βandIL‐18processingandrelease,isaligand‐gatedcationchannelthatisexpressedbymacrophages.InexperimentalCrgn,P2RX7deficiencyattenuatesrenalinjury,buttheunderlyingmechanismisunknown.Here,weshowthatP2RX7levelsandtheexpressionofseveralgenesbelongingtotheNlrp3‐inflammasomepathwayareup‐regulatedinthemacrophagesoftheWKYrat,astrainuniquelysusceptibletomacrophage‐dependentNTN.Importantly,followingP2RX7activation,WKYBMDMsproducemarkedlyincreasedlevelsofactivecaspase‐1,IL‐1β,andIL‐18whencomparedwiththeNTN‐resistantLEWratBMDMs.P2RX7andactiveIL‐1β,IL‐18,andcaspase‐1proteinlevelsweremarkedlyincreasedintheWKYnephriticglomeruli4daysfollowinginductionofNTN,andtheuseofaP2RX7antagonistreducedthelevelsofsecretedactiveIL‐1β.Interestingly,thepost‐translationalcontrolofP2RX7‐mediatedinflammasomeactivationisunderthegeneticregulationoftwopreviouslyidentifiedCrgnquantitativetraitlociintheBMDMsandnephriticglomerulioftheWKYrat.Inconclusion,weproposeanovelmechanism,wherebygeneticallydeterminedP2RX7levelsinmacrophagesregulateNlrp3‐inflammasomeactivationandsusceptibilitytoCrgn...

[学科分类] 生理学

[关键词] WKY rat;IL‐1βcaspase‐1;IL‐18;glomeruli