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Published on: May 12, 2023
Myeloid nuclear differentiation antigen, neutrophil apoptosis and sepsis
Eric Milot1, Nasser Fotouhi-Ardakani, János G Filep
1Department of Medicine, Maisonneuve-Rosemont Hospital Research Center, University of Montréal Montréal, QC, Canada.
Abstract:
Sepsis and septic shock are characterized by prolonged inflammation and delayed resolution, which are associated with suppression of neutrophil apoptosis. The role of the intrinsic apoptotic pathway and intracellular factors in regulation of neutrophil apoptosis remain incompletely understood. We previously reported that the nuclear factor MNDA (myeloid nuclear differentiation antigen) is fundamental to execution of the constitutive neutrophil death program. During neutrophil apoptosis MNDA is cleaved by caspases and relocated to the cytoplasm. However, when challenged with known mediators of sepsis, human neutrophils of healthy donors or neutrophils from patients with sepsis exhibited impaired MNDA relocation/cleavage parallel with myeloid cell leukemia-1 (MCL-1) accumulation and suppression of apoptosis. MNDA knockdown in a model cell line indicated that upon induction of apoptosis, MNDA promotes proteasomal degradation of MCL-1, thereby aggravating mitochondrial dysfunction. Thus, MNDA is central to a novel nucleus-mitochondrion circuit that promotes progression of apoptosis. Disruption of this circuit contributes to neutrophil longevity, thereby identifying MNDA as a potential therapeutic target in sepsis and other inflammatory pathologies.
Insights
Myeloid nuclear differentiation antigen (MNDA) normally triggers neutrophil apoptosis. In sepsis, impaired MNDA function leads to neutrophil survival, promoting inflammation and suggesting MNDA as a therapeutic target.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Sepsis and septic shock involve prolonged inflammation and delayed resolution.
- Suppressed neutrophil apoptosis contributes to these inflammatory processes.
- The intrinsic apoptotic pathway's role in neutrophil apoptosis is not fully understood.
Purpose of the Study:
- To investigate the role of myeloid nuclear differentiation antigen (MNDA) in neutrophil apoptosis during sepsis.
- To elucidate the mechanism by which MNDA regulates neutrophil apoptosis and its connection to intracellular factors.
Main Methods:
- Analysis of MNDA cleavage and relocation in human neutrophils from healthy donors and sepsis patients.
- Assessment of myeloid cell leukemia-1 (MCL-1) levels in relation to MNDA function.
- MNDA knockdown in a model cell line to study its effect on MCL-1 degradation and mitochondrial function.
Main Results:
- Neutrophils from sepsis patients showed impaired MNDA relocation and cleavage.
- This impairment correlated with increased MCL-1 accumulation and suppressed apoptosis.
- MNDA promotes MCL-1 proteasomal degradation, aggravating mitochondrial dysfunction during apoptosis induction.
Conclusions:
- MNDA is essential for a nucleus-mitochondrion circuit that drives apoptosis progression.
- Disruption of this MNDA-mediated circuit leads to neutrophil longevity in sepsis.
- MNDA represents a potential therapeutic target for sepsis and other inflammatory diseases.
