Induction of NLRP3 Inflammasome Activation by Heme in Human Endothelial Cells

• Published in: Oxidative medicine and cellular longevity Vol. 2018; no. 2018; pp. 1 - 14
• Main Authors: Jeney, Viktória, Cordero, Mario D., Ryffel, Bernhard, Bányai, Emese, Nyakundi, Benard Bogonko, Balogh, Enikő, Tóth, Andrea, Erdei, Judit, Paragh, György
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2018; Hindawi; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Age; Apoptosis; Atherosclerosis; Blood; Cellular biology; Diabetes; Diabetic retinopathy; Endothelium; Ethylenediaminetetraacetic acid; Flow cytometry; Heme; Hemoglobin; Immunology; Inflammation; Life Sciences; Mice; Neutrophils; Rodents; Tumor necrosis factor-TNF; Veins & arteries; United States > US
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2018/4310816

Hemolytic or hemorrhagic episodes are often associated with inflammation even when infectious agents are absent suggesting that red blood cells (RBCs) release damage-associated molecular patterns (DAMPs). DAMPs activate immune and nonimmune cells through pattern recognition receptors. Heme, released from RBCs, is a DAMP and induces IL-1β production through the activation of the nucleotide-binding domain and leucine-rich repeat-containing family and pyrin domain containing 3 (NLRP3) in macrophages; however, other cellular targets of heme-mediated inflammasome activation were not investigated. Because of their location, endothelial cells can be largely exposed to RBC-derived DAMPs; therefore, we investigated whether heme and other hemoglobin- (Hb-) derived species induce NLRP3 inflammasome activation in these cells. We found that heme upregulated NLRP3 expression and induced active IL-1β production in human umbilical vein endothelial cells (HUVECs). LPS priming largely amplified the heme-mediated production of IL-1β. Heme administration into C57BL/6 mice induced caspase-1 activation and cleavage of IL-1β which was not observed in NLRP3−/− mice. Unfettered production of reactive oxygen species played a critical role in heme-mediated NLRP3 activation. Activation of NLRP3 by heme required structural integrity of the heme molecule, as neither protoporphyrin IX nor iron-induced IL-1β production. Neither naive nor oxidized forms of Hb were able to induce IL-1β production in HUVECs. Our results identified endothelial cells as a target of heme-mediated NLRP3 activation that can contribute to the inflammation triggered by sterile hemolysis. Thus, understanding the characteristics and cellular counterparts of RBC-derived DAMPs might allow us to identify new therapeutic targets for hemolytic diseases.