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Frataxin attenuates endothelial inflammation triggered by engulfment of senescent erythrocytes
Xingyi Cheng1, Yi Cheng2, Chenglin Huang2
1Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
Background:
Hypertension is linked to a shortened erythrocyte lifespan, with endothelial cells acting as non-professional phagocytes to clear senescent erythrocytes. However, whether increased erythrophagocytosis contributes to endothelial inflammation remains unclear. Frataxin (FXN) plays a crucial role in controlling iron balance and metabolism. This study investigated the role of FXN-mediated iron engulfment in regulating endothelial pro-inflammatory phenotype.
Methods:
Hypertensive models were established by infusing angiotensin II (Ang II) into endothelial cell-specific Fxn knockout mice for 14 days. Erythrocyte senescence was evaluated using scanning electron microscopy and metabolomics. Endothelial erythrophagocytosis and inflammation were assessed via immunofluorescence staining. Integrated proteomics along with surface plasmon resonance (SPR) analyses were employed to identify key proteins and protein-protein interactions during erythrophagocytosis.
Results:
Erythrocytes from Ang II-infused mice displayed signs of senescence, including swelling and acanthocytic morphology. Metabolomics revealed a progressive metabolic decline in erythrocytes. Endothelial cells efficiently cleared senescent erythrocytes, while proteomics identified decreased FXN and increased thioredoxin-interacting protein (TXNIP) protein levels. Although FXN function did not affect phagocytosis efficiency, its absence led to mitochondrial iron overload, elevated lipid peroxides, and activation of the TXNIP/NLR family pyrin domain-containing 3 (NLRP3) inflammasome both in vivo and in vitro. Molecular docking showed FXN interacts with the thioredoxin-2 (TRX2)/TXNIP redoxisome, forming a trimeric complex. FXN acetylation at Lys-192 (FXNK192) caused TXNIP dissociation from oxidized TRX2, liberating TXNIP for NLRP3 activation. Furthermore, Fxn acetylation-deficient mice exhibited reduced endothelial oxidative stress and inflammation.
Conclusions:
Excessive endothelial erythrophagocytosis triggers NLRP3 inflammasome activation by destabilizing the FXN/TRX2/TXNIP complex.
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