Epigenetic Regulation of Neutrophils in ARDS
Acute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of react...
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2025-07-01
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| author | Jordan E. Williams Zannatul Mauya Virginia Walkup Shaquria Adderley Colin Evans Kiesha Wilson |
| author_facet | Jordan E. Williams Zannatul Mauya Virginia Walkup Shaquria Adderley Colin Evans Kiesha Wilson |
| author_sort | Jordan E. Williams |
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| description | Acute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). To identify targets for treatment, it was found that epigenetic mechanisms, including histone modifications, hypomethylation, hypermethylation, and non-coding RNAs, regulate neutrophil phenotypic plasticity, survival, and inflammatory potential. It has been identified that neutrophils in ARDS patients exhibit abnormal methylation patterns and are associated with altered gene expression and prolonged neutrophil activation, thereby contributing to sustained inflammation. Histone citrullination, particularly via PAD4, facilitates NETosis, while histone acetylation status modulates chromatin accessibility and inflammatory gene expression. MicroRNAs have also been shown to regulate neutrophil activity, with miR-223 and miR-146a potentially being biomarkers and therapeutic targets. Neutrophil heterogeneity, as evidenced by distinct subsets such as low-density neutrophils (LDNs), varies across ARDS etiologies, including COVID-19. Single-cell RNA sequencing analyses, including the use of trajectory analysis, have revealed transcriptionally distinct neutrophil clusters with differential activation states. These studies support the use of epigenetic inhibitors, including PAD4, HDAC, and DNMT modulators, in therapeutic intervention. While the field has been enlightened with new findings, challenges in translational application remain an issue due to species differences, lack of stratification tools, and heterogeneity in ARDS presentation. This review describes how targeting neutrophil epigenetic regulators could help regulate hyperinflammation, making epigenetic modulation a promising area for precision therapeutics in ARDS. |
| format | Article |
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| institution | Kabale University |
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| language | English |
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| spelling | doaj-art-942bfa3ff7624387b4d1be0bd3da40ed2025-08-20T03:36:03ZengMDPI AGCells2073-44092025-07-011415115110.3390/cells14151151Epigenetic Regulation of Neutrophils in ARDSJordan E. Williams0Zannatul Mauya1Virginia Walkup2Shaquria Adderley3Colin Evans4Kiesha Wilson5Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USADepartment of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USADepartment of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USADepartment of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29209, USADepartment of Cell Biology & Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USADepartment of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USAAcute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). To identify targets for treatment, it was found that epigenetic mechanisms, including histone modifications, hypomethylation, hypermethylation, and non-coding RNAs, regulate neutrophil phenotypic plasticity, survival, and inflammatory potential. It has been identified that neutrophils in ARDS patients exhibit abnormal methylation patterns and are associated with altered gene expression and prolonged neutrophil activation, thereby contributing to sustained inflammation. Histone citrullination, particularly via PAD4, facilitates NETosis, while histone acetylation status modulates chromatin accessibility and inflammatory gene expression. MicroRNAs have also been shown to regulate neutrophil activity, with miR-223 and miR-146a potentially being biomarkers and therapeutic targets. Neutrophil heterogeneity, as evidenced by distinct subsets such as low-density neutrophils (LDNs), varies across ARDS etiologies, including COVID-19. Single-cell RNA sequencing analyses, including the use of trajectory analysis, have revealed transcriptionally distinct neutrophil clusters with differential activation states. These studies support the use of epigenetic inhibitors, including PAD4, HDAC, and DNMT modulators, in therapeutic intervention. While the field has been enlightened with new findings, challenges in translational application remain an issue due to species differences, lack of stratification tools, and heterogeneity in ARDS presentation. This review describes how targeting neutrophil epigenetic regulators could help regulate hyperinflammation, making epigenetic modulation a promising area for precision therapeutics in ARDS.https://www.mdpi.com/2073-4409/14/15/1151ARDSneutrophilsepigeneticslncRNAmiRNAhistone modification |
| spellingShingle | Jordan E. Williams Zannatul Mauya Virginia Walkup Shaquria Adderley Colin Evans Kiesha Wilson Epigenetic Regulation of Neutrophils in ARDS Cells ARDS neutrophils epigenetics lncRNA miRNA histone modification |
| title | Epigenetic Regulation of Neutrophils in ARDS |
| title_full | Epigenetic Regulation of Neutrophils in ARDS |
| title_fullStr | Epigenetic Regulation of Neutrophils in ARDS |
| title_full_unstemmed | Epigenetic Regulation of Neutrophils in ARDS |
| title_short | Epigenetic Regulation of Neutrophils in ARDS |
| title_sort | epigenetic regulation of neutrophils in ards |
| topic | ARDS neutrophils epigenetics lncRNA miRNA histone modification |
| url | https://www.mdpi.com/2073-4409/14/15/1151 |
| work_keys_str_mv | AT jordanewilliams epigeneticregulationofneutrophilsinards AT zannatulmauya epigeneticregulationofneutrophilsinards AT virginiawalkup epigeneticregulationofneutrophilsinards AT shaquriaadderley epigeneticregulationofneutrophilsinards AT colinevans epigeneticregulationofneutrophilsinards AT kieshawilson epigeneticregulationofneutrophilsinards |