The xanthine oxidase-nfat5 pathway regulates macrophage activation and tlr-induced inflammatory arthritis
Open accessAbstract
NFAT5 (nuclear factor of activated T cells), a well‐known osmoprotective factor, can be activated by isotonic stimuli such as Toll‐like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO–ROS–p38 MAPK–NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO‐derived ROS were selectively required for the TLR‐induced NFAT5 activation and NFAT5 binding to the IL‐6 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in BALB/c mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL‐6 in splenic macrophages in C57BL/6 mice. Collectively, these data support a novel function of the XO–NFAT5 axis in macrophage activation and TLR‐induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis.
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Only a few studies investigated the role of xanthine oxidase in macrophages and suggested involvement in inflammasome activation, regulation of cytokine expression and defense against parasitic infection.
“however, only a few studies investigated its role in macrophages and suggested involvement in inflammasome activation [144], regulation of cytokine expression [145] and defense against parasitic infection [146].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [145]
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References 45 · Cited by 48
- Authors
- Kim, N., Choi, S., Han, E., Hong, B., Choi, S. Y., Kwon, H. M., Hwang, S., Cho, C., & Kim, W.
- Affiliations
- Catholic University of Korea (KR)
- Ulsan National Institute of Science and Technology (KR)
- Hankyong National University (KR)
- The Catholic University of Korea Seoul St. Mary's Hospital (KR)
- Corresponding author
- Kim, Wan‐Uk
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2014-08-11
- Volume
- 44
- Issue
- 9
- Pages
- 2721-2736
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W1509128008
- Cited by
- 48
- References
- 45
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 1
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Korea Health Industry Development Institute (HI09C1555)
- National Research Foundation of Korea (2009-0080087, 2011-0020163)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- xanthine oxidase, NFAT5, macrophage activation, Toll-like receptors, inflammatory arthritis, reactive oxygen species, p38 MAPK, IL-6 promoter, allopurinol, osmotic stress, RAW 264.7 macrophages, splenic macrophages
- MeSH terms
- Animals, Arthritis, Cell Line, Chronic Disease, Female, Gene Expression Regulation, Humans, Inflammation, Macrophage Activation, Macrophages, Male, Mice, Inbred BALB C, Transcription Factors, Xanthine Oxidase, Interleukin-6, Reactive Oxygen Species, Toll-Like Receptors, Mice
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