The impact of hemoglobin oxidation in NLRP3 inflammasome activation upon intravascular hemolysis

Abstract

In this work, we demonstrated that following intravascular hemolysis Hb oxidation leads to the formation of hemichrome, metHb, covalently cross-linked Hb multimers, and free heme. We showed that PHZ-induced IVH triggers IL-1 production via the NLRP3 inflammasome activation. We demonstrated that covalently cross-linked Hb forms during the decomposition of transient ferrylHb the molecules we proposed to name as gmoxHb. We Identified gmoxHb as a potent pro-inflammatory Hb form which induced the active production of IL-1 in vivo and in vitro. We confirmed that NLRP3 deficiency confers a survival advantage to mice in PHZ-induced IVH via increased tolerance and improved tissue damage control mechanisms. Identification of RBC-derived DAMPs and understanding the signaling mechanisms involved in the pathophysiology might provide new approaches for the treatment of IVH-related pathological conditions.