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  3. A newly developed PLD1 inhibitor ameliorates rheumatoid arthritis by regulating pathogenic T and B cells and inhibiting osteoclast differentiation

A newly developed PLD1 inhibitor ameliorates rheumatoid arthritis by regulating pathogenic T and B cells and inhibiting osteoclast differentiation

  • Immunol Lett. 2023 Sep 16:263:87-96. doi: 10.1016/j.imlet.2023.09.007.
Jin-Sil Park 1,  SeungCheon Yang 1,  Doona Song 2,  Sung-Min Kim 1,  JeongWon Choi 1,  Hye Yeon Kang 3,  Ha Yeon Jeong 3,  Gyoonhee Han 4,  Do Sik Min 5,  Mi-La Cho 6,  Sung-Hwan Park 7
Affiliations

Affiliations

  • 1 The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
  • 2 Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 3 The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
  • 4 Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea; Department of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
  • 5 Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea; Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea. Electronic address: [email protected].
  • 6 The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea Seoul 06591, Republic of Korea. Electronic address: [email protected].
  • 7 The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea. Electronic address: [email protected].
PMID: 37722567 DOI: 10.1016/j.imlet.2023.09.007
Abstract

Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, plays multiple roles in inflammation. We investigated the therapeutic effects of the newly developed PLD1 inhibitors A2998, A3000, and A3773 in vitro and in vivo rheumatoid arthritis (RA) model. A3373 reduced the levels of LPS-induced TNF-α, IL-6, and IgG in murine splenocytes in vitro. A3373 also decreased the levels of IFN-γ and IL-17 and the frequencies of Th1, Th17 cells and germinal-center B cells, in splenocytes in vitro. A3373 ameliorated the severity of collagen-induced arthritis (CIA) and suppressed infiltration of inflammatory cells into the joint tissues of mice with CIA compared with vehicle-treated mice. Moreover, A3373 prevented systemic bone demineralization in mice with CIA and suppressed osteoclast differentiation and the mRNA levels of osteoclastogenesis markers in vitro. These results suggest that A3373 has therapeutic potential for RA.

Keywords

Collagen-induced arthritis; Inflammatory cytokines; Osteoclastogenesis; Phospholipase D1; Rheumatoid arthritis.

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