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Targeting the MLKL-F-actin-NLRP3 axis attenuates arsenic-induced myocardial necroinflammation
Yinan Liu1, Yixin Cui2, Meng Zhang2
1Department of Spine and Bone Tumor, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, 710004, Shaanxi Province, People's Republic of China; School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, Xi'an, 710061, Shaanxi, People's Republic of China.
Abstract:
Arsenic, an environmental toxicant, causes myocardial inflammatory injury upon chronic low-dose exposure, though its mechanisms are not fully understood. Necroptosis, mediated by mixed lineage kinase domain-like protein (MLKL), promotes necroinflammation by activating the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Since F-actin depolymerization may regulate NLRP3, this study investigates its role in arsenite-induced cardiac injury. Wild-type (WT) and Mlkl-knockout (Mlkl-/-) C57BL/6 mice were exposed to arsenite (2.8-25.2 mg/L) for 8 weeks, while H9C2 cardiomyocyte were treated with arsenite (8-32 μM) for 24 h. Inhibitors targeting MLKL (Nec-1, GSK-872, NSA), NLRP3 (MCC950), and F-actin stabilization (Jasplakinolide) were employed. Arsenite dose-dependently upregulated p-MLKL and NLRP3 protein expression in myocardial tissues and H9C2 cells. Mlkl knockout or inhibition of necroptosis (Nec-1, GSK-872, and NSA) significantly suppressed NLRP3 activation and attenuated cardiac injury. Arsenite dose-dependently induced F-actin depolymerization and reduced actin expression, which was partially reversed in Mlkl-/- mice and necroptosis inhibitors. F-actin stabilizer Jasplakinolide markedly inhibited NLRP3 without affecting MLKL phosphorylation. Thus, chronic arsenite exposure promotes NLRP3 inflammasome activation via p-MLKL-mediated F-actin disruption, forming a "necroptosis-cytoskeletal disruption-inflammation" cascade. Targeting the MLKL-F-actin-NLRP3 axis offers a novel strategy for preventing and treating arsenic-induced myocardial damage.
Insights
Chronic arsenic exposure causes heart injury by activating necroptosis (programmed cell death) and the NLRP3 inflammasome, disrupting F-actin. Targeting this pathway may prevent arsenic-induced cardiac damage.
Area of Science:
- Toxicology
- Cardiovascular Biology
- Cellular Biology
Background:
- Arsenic is an environmental toxicant causing myocardial inflammatory injury.
- The mechanisms underlying arsenic-induced cardiac damage, particularly the roles of necroptosis and the NLRP3 inflammasome, are not fully understood.
- F-actin depolymerization is a potential regulator of NLRP3 inflammasome activation.
Purpose of the Study:
- To investigate the role of F-actin depolymerization in arsenite-induced cardiac injury.
- To elucidate the relationship between necroptosis, F-actin disruption, and NLRP3 inflammasome activation in the context of arsenic exposure.
Main Methods:
- Exposure of wild-type and Mlkl-knockout mice and H9C2 cardiomyocytes to arsenite.
- Utilized inhibitors for MLKL (Nec-1, GSK-872, NSA), NLRP3 (MCC950), and F-actin stabilization (Jasplakinolide).
- Assessed protein expression of p-MLKL and NLRP3, F-actin depolymerization, and cardiac injury markers.
Main Results:
- Arsenite upregulated p-MLKL and NLRP3 in a dose-dependent manner.
- MLKL knockout or inhibition of necroptosis suppressed NLRP3 activation and reduced cardiac injury.
- Arsenite induced F-actin depolymerization, which was partially reversed by MLKL knockout or necroptosis inhibition.
- F-actin stabilization inhibited NLRP3 activation without affecting MLKL phosphorylation.
Conclusions:
- Chronic arsenite exposure triggers a "necroptosis-cytoskeletal disruption-inflammation" cascade.
- Arsenite promotes NLRP3 inflammasome activation via MLKL-mediated F-actin disruption.
- Targeting the MLKL-F-actin-NLRP3 axis presents a novel therapeutic strategy for arsenic-induced myocardial damage.
