Heme Induces IL-1β Secretion Through Activating NLRP3 in Kidney Inflammation

• Published in: Cell biochemistry and biophysics Vol. 69; no. 3; pp. 495 - 502
• Main Authors: Li, Qianwei, Fu, Weihua, Yao, Jiwei, Ji, Zheng, Wang, Yongquan, Zhou, Zhansong, Yan, Junan, Li, Weibing
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.07.2014
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biological and Medical Physics; Biomedical and Life Sciences; Biophysics; Biotechnology; CARD Signaling Adaptor Proteins; Carrier Proteins - metabolism; Caspase 1 - metabolism; Cell Biology; Heme - metabolism; Inflammasomes - metabolism; Inflammation - complications; Inflammation - immunology; Inflammation - metabolism; Interleukin-1beta - secretion; Kidney - metabolism; Life Sciences; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - secretion; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Original Paper; Pharmacology/Toxicology; Receptors, Purinergic P2X - metabolism; Ureteral Obstruction - complications; Kidney inflammation; NLRP3 inflammasome; IL-1β; Heme
• ISSN: 1085-9195; 1559-0283
• DOI: 10.1007/s12013-014-9823-9

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 P2X 7 R and P2X 4 R. 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.