Platelet activation and ferroptosis mediated NETosis drives heme induced pulmonary thrombosis

NaveenKumar, SK and Hemshekhar, M and Sharathbabu, BN and Kemparaju, K and Mugesh, G and Girish, KS (2023) Platelet activation and ferroptosis mediated NETosis drives heme induced pulmonary thrombosis. In: Biochimica et Biophysica Acta - Molecular Basis of Disease, 1869 (5).

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Abstract

Cell-free heme (CFH) is a product of hemoglobin, myoglobin and hemoprotein degradation, which is a hallmark of pathologies associated with extensive hemolysis and tissue damage. CHF and iron collectively induce cytokine storm, lung injury, respiratory distress and infection susceptibility in the lungs suggesting their key role in the progression of lung disease pathology. We have previously demonstrated that heme-mediated reactive oxygen species (ROS) induces platelet activation and ferroptosis. However, interaction of ferroptotic platelets and neutrophils, the mechanism of action and associated complications remain unclear. In this study, we demonstrate that heme-induced P-selectin expression and Phosphatidylserine (PS) externalization in platelets via ASK-1-inflammasome axis increases platelet-neutrophil aggregates in circulation, resulting in Neutrophil extracellular traps (NET) formation in vitro and in vivo. Further, heme-induced platelet activation in mice increased platelet-neutrophil aggregates and accumulation of NETs in the lungs causing pulmonary damage. Thus, connecting CFH-mediated platelet activation to NETosis and pulmonary thrombosis. As lung infections induce acute respiratory stress, thrombosis and NETosis, we propose that heme -mediated platelet activation and ferroptosis might be crucial in such clinical manifestations. Further, considering the ability of redox modulators and ferroptosis inhibitors like FS-1, Lpx-1 and DFO to inhibit heme-induced ferroptotic platelets-mediated NETosis and pulmonary thrombosis. They could be potential adjuvant therapy to regulate respiratory distress-associated clinical complications. © 2023

Item Type:	Journal Article
Publication:	Biochimica et Biophysica Acta - Molecular Basis of Disease
Publisher:	Elsevier B.V.
Additional Information:	The copyright for this article belongs to Elsevier B.V.
Keywords:	Ferroptosis; Heme; Neutrophil extracellular traps; Platelets; Pulmonary damage
Department/Centre:	Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited:	21 Apr 2023 10:01
Last Modified:	21 Apr 2023 10:01
URI:	https://eprints.iisc.ac.in/id/eprint/81357

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