Apurinic/apyrimidinic endonuclease 1 alleviates inflammation in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Ha-Reum Lee; Su-Jin Yoo; Jinhyun Kim; Yu Ran Lee; Hee Kyoung Joo; Byeong Hwa Jeon; Seong Wook Kang

doi:10.5114/ceji.2024.141946

eISSN: 1644-4124
ISSN: 1426-3912

Central European Journal of Immunology

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2/2024
vol. 49

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abstract:

Basic research

Apurinic/apyrimidinic endonuclease 1 alleviates inflammation in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Ha-Reum Lee

^{1, 2}

,

Su-Jin Yoo

^{1, 2}

,

Jinhyun Kim

^{1, 2}

,

Yu Ran Lee

¹

,

Hee Kyoung Joo

¹

,

Byeong Hwa Jeon

¹

,

Seong Wook Kang

^{1, 2}

Chungnam National University, South Korea
Chungnam National University Hospital, South Korea

Cent Eur J Immunol 2024; 49 (2): 113-125

DOI: https://doi.org/10.5114/ceji.2024.141946

Online publish date: 2024/08/26

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Introduction:
Apurinic/apyrimidinic endonuclease 1 (APEX1) is a protein with elevated expression in synovial fluids from rheumatoid arthritis (RA) patients. However, its role in RA pathogenesis remains unexplored. This study investigated the influence of APEX1 on inflammatory pathways in fibroblast-like synoviocytes (FLS) isolated from RA patients.

Material and methods:
FLS from RA patients (n = 5) were stimulated with recombinant tumor necrosis factor α (TNF-α) and interleukin (IL)-17. Subsequently, cells were treated with recombinant APEX1, and assessments were made on reactive oxygen species (ROS) production and mitochondrial membrane potential. Additionally, mRNA levels of IL-1 family members were quantified. Cell migration was evaluated through Transwell chamber assays, and levels of key secreted inflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA).

Results:
The results demonstrated that APEX1 significantly reduced mitochondrial-specific ROS expression and restored mitochondrial membrane potential in TNF-α/IL-17-stimulated RA FLS. Furthermore, APEX1 treatments attenuated TNF-α/IL-17-induced activation of p38 MAPK, NF-κB, and PI3K 110δ signaling pathways. Similarly, APEX1 significantly diminished TNF-α/IL-17-induced expression of inflammatory cytokines, including IL-1 family members, IL-6, IL-8, and vascular endothelial growth factor (VEGF). Notably, APEX1 downregulated cell migration of TNF-α/IL-17-treated RA FLS via inhibition of matrix metalloproteinase 3 (MMP3).

Conclusions:
These findings collectively underscore the role of APEX1 as a key mediator of cytokine-amplified migration, modulating ROS and MMP3 in RA FLS, thus supporting its potential as a therapeutic target in RA treatment.

keywords:

Apurinic/apyrimidinic endonuclease 1 alleviates inflammation in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Ha-Reum Lee 1, 2 , Su-Jin Yoo 1, 2 , Jinhyun Kim 1, 2 , Yu Ran Lee 1 , Hee Kyoung Joo 1 , Byeong Hwa Jeon 1 , Seong Wook Kang 1, 2

rheumatoid arthritis, inflammation, migration, reactive oxygen species, fibroblast-like synoviocytes

Ha-Reum Lee

^{1, 2}

,

Su-Jin Yoo

^{1, 2}

,

Jinhyun Kim

^{1, 2}

,

Yu Ran Lee

¹

,

Hee Kyoung Joo

¹

,

Byeong Hwa Jeon

¹

,

Seong Wook Kang

^{1, 2}