Phorbol 12-myristate 13-acetate stimulation under hypoxia induces nuclear swelling with DNA outflow but not extracellular trap formation of neutrophils.

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Masuda S, Kato K, Ishibashi M, Nishibata Y, Sugimoto A, Nakazawa D, Tanaka S, Tomaru U, Tsujino I, Ishizu A

Phorbol 12-myristate 13-acetate stimulation under hypoxia induces nuclear swelling with DNA outflow but not extracellular trap formation of neutrophils.

Exp Mol Pathol. 2022 Apr;125:104754. doi: 10.1016/j.yexmp.2022.104754. Epub 2022 Mar 5.

PubMed ID
35259405 [ View in PubMed
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Abstract

Neutrophils stand sentinel over infection and possess diverse antimicrobial weapons, including neutrophil extracellular traps (NETs). NETs are composed of web-like extracellular DNA decorated with antimicrobial substances and can trap and eliminate invading microorganisms. Although phorbol 12-myristate 13-acetate (PMA) is a potent NET inducer, previous studies have demonstrated that not all neutrophils exhibit NET formation even if stimulated by PMA at high concentrations. This study first showed that some neutrophils stimulated by PMA displayed a swollen nucleus but not NET formation and that hypoxic environments suppressed the NET release. Next, characterization of PMA-stimulated neutrophils with a swollen nucleus was accomplished by differentiating between suicidal-type NETosis and apoptosis. Furthermore, the significance of the phenomenon was examined using formalin-fixed, paraffin-embedded human lung disease tissues with and without pneumonia. As a result, histone H3 citrullination, DNA outflow, propidium iodide labeling, resistance to DNase I, and suspended actin rearrangement were characteristics of PMA-stimulated neutrophils with a swollen nucleus distinct from neutrophils that underwent either suicidal-type NETosis or apoptosis. Neutrophils stimulated by PMA under hypoxic conditions secreted matrix metalloproteinase-9 cytotoxic to human lung-derived fibroblasts. Further, deposition of neutrophil-derived citrullinated histone H3(+) chromatin substances in pulmonary lesions was greater in patients with pneumonia than in patients without pneumonia and positively correlated with hypoxia-inducible factor-1alpha expression. The collective findings suggested that neutrophils activated under hypoxic conditions could be putative modulators of hypoxia-related disease manifestations.

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