Heme induces IL-1β secretion through activating NLRP3 in kidney inflammation.
To produce proinflammatory master cytokine IL-1β in macrophages, two stimulation pathways are needed including TLRs-NF-κB axis and NLRPs/ASC-caspase-1 axis. Different signals including exogenous and endogenous trigger inflammatory response distinctly. Among them, the role of endogenous stimulators of inflammation is poorly understood. As a component of hemoglobin, free heme is released when hemolysis or extensive cell damage occur which results in inflammatory response. Here, we find that heme induces IL-1β secretion through activating NLRP3 inflammasome in macrophages. Heme activates NLRP3 through P2X receptors, especially the P2X7R and P2X4R. Most importantly, significantly enhancement of heme level and activation of NLRPs/ASC-caspase-1 axis were observed in mice kidney after unilateral ureteral obstruction which could be inhibited by enforced expression of heme oxygenase-1 (HO-1). Our study proves that heme is a potential danger activator of NLRP3 inflammasome that plays an essential role in IL-1β secretion during kidney inflammation and provides new insight into the mechanism of innate immune initiation. Further investigation will be beneficial to develop new molecular target and molecular diagnosis indicator in therapy of kidney inflammation.
Department of Urology, Southwest Hospital, Third Military Medical University, 30, Gao TanYan, Chongqing, 400038, People's Republic of China.
Qianwei
Q
Li
Weihua
W
Fu
Jiwei
J
Yao
Zheng
Z
Ji
Yongquan
Y
Wang
Zhansong
Z
Zhou
Junan
J
Yan
Weibing
W
Li
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058469:Receptors, Purinergic P2X / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D058469:Receptors, Purinergic P2X; D006418:Heme; D020170:Caspase 1