| First Author | Nyakundi BB | Year | 2019 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1865 |
| Issue | 2 | Pages | 464-475 |
| PubMed ID | 30389578 | Mgi Jnum | J:270167 |
| Mgi Id | MGI:6277273 | Doi | 10.1016/j.bbadis.2018.10.030 |
| Citation | Nyakundi BB, et al. (2019) Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1beta production upon intravascular hemolysis. Biochim Biophys Acta Mol Basis Dis 1865(2):464-475 |
| abstractText | Damage associated molecular patterns (DAMPs) are released form red blood cells (RBCs) during intravascular hemolysis (IVH). Extracellular heme, with its pro-oxidant, pro-inflammatory and cytotoxic effects, is sensed by innate immune cells through pattern recognition receptors such as toll-like receptor 4 and nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3), while free availability of heme is strictly controlled. Here we investigated the involvement of different hemoglobin (Hb) forms in hemolysis-associated inflammatory responses. We found that after IVH most of the extracellular heme molecules are localized in oxidized Hb forms. IVH was associated with caspase-1 activation and formation of mature IL-1beta in plasma and in the liver of C57BL/6 mice. We showed that ferrylHb (FHb) induces active IL-1beta production in LPS-primed macrophages in vitro and triggered intraperitoneal recruitment of neutrophils and monocytes, caspase-1 activation and active IL-1beta formation in the liver of C57BL/6 mice. NLRP3 deficiency provided a survival advantage upon IVH, without influencing the extent of RBC lysis or the accumulation of oxidized Hb forms. However, both hemolysis-induced and FHb-induced pro-inflammatory responses were largely attenuated in Nlrp3(-/-) mice. Taken together, FHb is a potent trigger of NLRP3 activation and production of IL-1beta in vitro and in vivo, suggesting that FHb may contribute to hemolysis-induced inflammation. Identification of RBC-derived DAMPs might allow us to develop new therapeutic approaches for hemolytic diseases. |
