Molecular Mechanisms for Regulation
of Neutrophil Apoptosis under Normal and Pathological Conditions

Noseykina, E M; Schepetkin, Igor A.; Atochin, Dmitriy N.

doi:10.1134/s0022093021030017

Cited by 8 publications

(10 citation statements)

References 144 publications

(273 reference statements)

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“…Thus, in response to PMA, AQP4 + NMOSD neutrophils showed higher survival rates, seemed to be partly retained in the phase of early apoptosis, showed diminished inhibition of caspase-3 activation, but were able to undergo NETosis. A prolonged neutrophil survival or delay in neutrophil apoptosis has been reported in several inflammatory diseases [ 49 ] such as ANCA-AAV [ 50 ], rheumatoid arthritis (RA) [ 29 , 50 ], cystic fibrosis [ 48 ], inflammatory bowel disease [ 51 ], lung cancer [ 52 ], sepsis [ 53 ] and acute pancreatitis [ 54 ]. In contrast to these reports that evaluated spontaneous apoptosis at later timepoints (24 h) [ 48 , 50 , 52 ], we observed, at an earlier time point of culture, an impaired cell death only in neutrophils stimulated with PMA.…”

Section: Discussionmentioning

confidence: 99%

“…This is in line with the reported increased IL-10 levels in CSF from AQP4 + NMOSD patients but not in MOGAD patients [ 61 ]. IL-10 is considered an anti-inflammatory cytokine, which seems to inhibit the GM-CSF-mediated anti-apoptotic effects [ 49 ]. However, in our setup, the survival of activated neutrophils in AQP4 + NMOSD may increase in response to GM-CSF but fails to be down-modulated by IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophil apoptosis can be modulated by internal signals (ROS) [49] and external signals such as cytokines GM-CSF, IL-6, IL-8, IL-15 and TNF-ɑ [56][57][58]. Additionally, IL-10 has been associated with an increase in apoptosis rates in vivo [56].…”

Section: Discussionmentioning

confidence: 99%

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Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD

Schroeder-Castagno

Rio-Serrato

Wilhelm

et al. 2022

J Neuroinflammation

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Background In neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neutrophils are found in CNS lesions. We previously demonstrated that NMOSD neutrophils show functional deficiencies. Thus, we hypothesized that neutrophil accumulation in the CNS may be facilitated by impairments affecting mechanisms of neutrophil death. Objective To evaluate cell death in blood neutrophils from aquaporin-4 (AQP4)-IgG-seropositive NMOSD and MOGAD patients as well as matched healthy controls (HC) using in vitro assays. Methods Twenty-eight AQP4 + NMOSD and 19 MOGAD patients in stable disease phase as well as 45 age- and sex-matched HC were prospectively recruited. To induce cell death, isolated neutrophils were cultured with/without phorbol 12-myristate 13-acetate (PMA). Spontaneous and PMA-induced NETosis and apoptosis were analyzed using 7-AAD and annexin-V by flow cytometry. Caspase-3 was assessed by western blot. Myeloperoxidase-DNA complexes (MPO-DNA), MPO and elastase were evaluated by ELISA, and cell-free DNA (cfDNA) by a fluorescence-based assay. Reactive oxygen species (ROS) were evaluated by a dihydrorhodamine 123-based cytometric assay. Serum GM-CSF, IL-6, IL-8, IL-15, TNF-ɑ and IL-10 were evaluated by multiplex assays, and neurofilament light chain (NfL) by single-molecule array assay. Results In response to PMA, neutrophils from AQP4 + NMOSD but not from MOGAD patients showed an increased survival, and subsequent reduced cell death (29.6% annexin V+ 7-AAD+) when compared to HC (44.7%, p = 0.0006). However, AQP4 + NMOSD also showed a mild increase in annexin V+ 7-AAD− early apoptotic neutrophils (24.5%) compared to HC (20.8%, p = 0.048). PMA-induced reduction of caspase-3 activation was more pronounced in HC (p = 0.020) than in AQP4 + NMOSD neutrophils (p = 0.052). No differences were observed in neutrophil-derived MPO-DNA or serum levels of MPO, elastase, IL-6, IL-8 and TNF-ɑ. IL-15 levels were increased in both groups of patients. In AQP4 + NMOSD, an increase in cfDNA, GM-CSF and IL-10 was found in serum. A positive correlation among cfDNA and NfL was found in AQP4 + NMOSD. Conclusions AQP4 + NMOSD neutrophils showed an increased survival capacity in response to PMA when compared to matched HC neutrophils. Although the data indicate that the apoptotic but not the NETotic response is altered in these neutrophils, additional evaluations are required to validate this observation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD

Schroeder-Castagno

Rio-Serrato

Wilhelm

et al. 2022

J Neuroinflammation

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“…Under physiological conditions, neutrophils ultimately enter the apoptotic stage, accompanied by a reduction in the expression of surface receptors and adhesion molecules and the release of chemokines 153 . Therefore, their biological efficacy is weakened to avoid possible damage to the body induced by the hyperactivity of neutrophil function to a certain extent 154 . Morphologically, we can observe a series of characteristic changes, including membrane blebs, cell body shrinkage, cytoplasmic compaction, nuclear chromatin condensation, and genomic DNA cleavage by endonuclease 155 …”

Section: Apoptosismentioning

confidence: 99%

“…153 Therefore, their biological efficacy is weakened to avoid possible damage to the body induced by the hyperactivity of neutrophil function to a certain extent. 154 Morphologically, we can observe a series of characteristic changes, including membrane blebs, cell body shrinkage, cytoplasmic compaction, nuclear chromatin condensation, and genomic DNA cleavage by endonuclease. 155…”

Section: Ap Op Tos Ismentioning

confidence: 99%

A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases

Li,

Wu,

Huang

et al. 2023

Immunological Reviews

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SummaryNeutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in‐depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment. This review explores the multifaceted processes and characteristics of neutrophil death, with a focus on tailored investigations within various autoimmune diseases. It also highlights the potential interplay between neutrophil death and the landscape of autoimmune disorders. The review encapsulates the pertinent pathways implicated in various neutrophil death mechanisms across diverse autoimmune diseases while also charts possible avenues for future research.

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Drug repurposing of cyclin-dependent kinase inhibitors for neutrophilic acute respiratory distress syndrome and psoriasis

Chen,

Lin

et al. 2024

Journal of Advanced Research

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Molecular Mechanisms for Regulation of Neutrophil Apoptosis under Normal and Pathological Conditions

Cited by 8 publications

References 144 publications

Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD

Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD

A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases

Drug repurposing of cyclin-dependent kinase inhibitors for neutrophilic acute respiratory distress syndrome and psoriasis

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