Myeloid nuclear differentiation antigen, neutrophil apoptosis and sepsis

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.

Keywords: MCL-1; MNDA; inflammation; internal apoptosis pathway; mitochondria; neutrophils; sepsis.

FIGURE 1

Proposed model for MNDA regulation of neutrophil apoptosis. Cytoplasmic relocation and cleavage of MNDA results in aggravation of mitochondrial dysfunction through promotion of proteasomal degradation of MCL-1. Activation of this novel nucleus-mitochondrion circuit would then accelerate execution of the apoptotic death program. Conversely, prevention of MNDA relocation and cleavage would prolong neutrophil survival by retarding apoptosis. The mechanisms by which bacterial components and/or inflammatory modulators could negatively influence MNDA relocation and cleavage and hence, interfere with this nuclear-mitochondrial circuit remains to be defined. Broken line indicates yet undefined mechanism.