A Role for Chlorinated Nucleosides in the Perturbation of Macrophage Function and Promotion of Inflammation
Abstract
During inflammation, myeloperoxidase released from activated phagocytes generates the highly reactive oxidant hypochlorous acid (HOCl). This oxidant plays an important role in the immune response but can also promote tissue damage and has been strongly linked with the development of numerous inflammatory diseases. HOCl reacts with cellular DNA forming chlorinated nucleobases, which induce strand breaks, mutations, and cross-links. Although it has been shown that chlorinated nucleosides are present within inflammatory pathologies and diseased tissue, whether or not these species are biomarkers formed as a byproduct of chronic inflammation or play a role in the disease progression has not been ascertained. In this study, we show that exposure of J774A.1 macrophage-like cells to chlorinated ribose and deoxyribose nucleosides results in the incorporation of 5-chloro-cytidine (5ClC), 8-chloro-adenosine (8ClA), and 8-chloro-guanosine (8ClG) into the cellular RNA and 5-chloro-deoxycytidine (5CldC) but not 8-chloro-deoxyguanosine (8CldG) or 8-chloro-deoxyadenosine (8CldA) into cellular DNA. Evidence was obtained for the clearance of 5ClC from the RNA, with a loss of 8ClA and 8ClG observed to a lesser extent, whereas an increase in the level of 5CldC in DNA was seen on further incubation of treated cells in the absence of chlorinated nucleosides. Importantly, exposure of the macrophages to chlorinated nucleosides, particularly 8ClG and 5ClC, resulted in the increased expression of interleukin-1β, and other pro-inflammatory cytokines and chemokines. With 5ClC, this inflammatory response was associated with the increased nuclear translocation of the NF-κB subunit, p65, rather than inflammasome activation. This alteration in gene expression appeared to be unrelated to the extent of incorporation of the chlorinated nucleosides into RNA or DNA and was not associated with any significant changes in cell viability or proliferation. Taken together, these results highlight a potential biological role for chlorinated nucleosides to promote inflammatory disease, in addition to their utility as biomarkers.
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Nucleic acids are important targets of chlorination stress with possible mutagenic, genotoxic, and cytotoxic outcomes downstream of chemical modification.
“Nucleic acids are important targets of chlorination stress with possible mutagenic, genotoxic, and cytotoxic outcomes downstream of chemical modification ( Figure 3C ) (39, 100–102).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [102]
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- Authors
- Macer-Wright, J. L., Stanley, N. R., Portman, N., Tan, J. T., Bursill, C., Rayner, B. S., & Hawkins, C. L.
- Affiliations
- The University of Sydney (AU)
- The Heart Research Institute (AU)
- University of Copenhagen (DK)
- Corresponding author
- Hawkins, Clare L.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-05-08
- Volume
- 32
- Issue
- 6
- Pages
- 1223-1234
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- OpenAlex
- W2944498471
- Cited by
- 18
- References
- 46
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 1
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- University of Sydney
- Australian Research Council (FT120100682)
- Novo Nordisk Foundation (NNF17OC0028990)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- hypochlorous acid, myeloperoxidase, macrophages, inflammation, 8-chloroadenosine, RNA incorporation, DNA incorporation, p65 nuclear translocation, IL-1β, inflammatory cytokines, chemokines, biomarkers, DNA strand breaks
- MeSH terms
- Animals, Cells, Cultured, Hypochlorous Acid, Inflammation, Macrophages, Nucleosides, Mice, Halogenation
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