Abstract
Polymorphonuclear neutrophils (PMNs) play a key role in host defense. However, their massive accumulation at the site of inflammation can delay regenerative healing processes and can initiate pathological inflammatory processes. Thus, the efficient clearance of PMNs mediated by the induction of regulated cell death is a key process preventing the development of these pathological conditions. Myeloperoxidase (MPO), a highly abundant enzyme in PMN granules, primarily connected with PMN defense machinery, is suggested to play a role in PMN-regulated cell death. However, the contribution of MPO to the mechanisms of PMN cell death remains incompletely characterized. Herein, the process of the cell death of mouse PMNs induced by three different stimuli – phorbol 12-myristate 13-acetate (PMA), opsonized streptococcus (OST), and N-formyl-met-leu-phe (fMLP) – was investigated. MPO-deficient PMNs revealed a significantly decreased rate of cell death characterized by phosphatidylserine surface exposure and cell membrane permeabilization. An inhibitor of MPO activity, 4-aminobenzoic acid hydrazide, did not exhibit a significant effect on PMA-induced cell death compared to MPO deficiency. Interestingly, only the limited activation of markers related to apoptotic cell death was observed (e.g. caspase 8 activation, Bax expression) and they mostly did not correspond to phosphatidylserine surface exposure. Furthermore, a marker characterizing autophagy, cleavage of LC3 protein, as well as histone H3 citrullination and its surface expression was observed. Collectively, the data show the ability of MPO to modulate the life span of PMNs primarily through the potentiation of cell membrane permeabilization and phosphatidylserine surface exposure.
Highlights
The inflammatory process is primarily protective and vital to health
The results suggest a new regulatory role on the part of MPO in the process of PS externalization and membrane permeabilization related to polymorphonuclear neutrophils (PMNs) cell death, which reveals the characteristics of different types of regulated cell death including apoptosis, autophagy, and NETosis
To evaluate the effect of MPO-derived oxidants in the course of PMN cell death, PMNs isolated from lung lavage of WT and MPO-/- mice were stimulated by selected activators of oxidative burst, phorbol 12-myristate 13-acetate (PMA), opsonized streptococcus (OST), and fMLP
Summary
The inflammatory process is primarily protective and vital to health. inflammation unrestrained in amplitude or duration leads to the development of pathological conditions and diseases. The predominant regulated cell death of PMNs in this process is considered apoptosis [3, 4]. The apoptosis of PMNs shares many morphological features with apoptosis in other cell types characterized by the exposure of phosphatidylserine (PS) on the outer leaflet of the cell membrane, the activation of caspases, DNA fragmentation, cytoplasmic condensation, membrane blebbing, and the formation of apoptotic bodies [5]. PS externalization is considered a general phenomenon in cells undergoing apoptosis, a few instances of apoptosis in the absence of PS exposure have been described. The intrinsic pathway of apoptosis is regulated by Bcl-2 family proteins. The activation of Bax and Bak proteins leads to the induction of mitochondrial outer membrane permeabilization, caspase activation, and apoptosis [7]
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