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Cell death and differentiation
Dec, 2024;31 (12): 1679-1694.

Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation.

Jiyeon Lee, Fumiyuki Sasaki, Eri Koike, Minjeong Cho, Yeongun Lee, So Hee Dho, Jina Lee, Eunji Lee, Eri Toyohara, Mika Sunakawa, Mariko Ishibashi, Huynh Hiep Hung, Saki Nishioka, Ritsuko Komine, Chiaki Okura, Masumi Shimizu, Masahito Ikawa, Akihiko Yoshimura, Rimpei Morita, Lark Kyun Kim
Author Information
  1. Jiyeon Lee: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  2. Fumiyuki Sasaki: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  3. Eri Koike: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  4. Minjeong Cho: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  5. Yeongun Lee: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  6. So Hee Dho: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  7. Jina Lee: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  8. Eunji Lee: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  9. Eri Toyohara: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  10. Mika Sunakawa: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  11. Mariko Ishibashi: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  12. Huynh Hiep Hung: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  13. Saki Nishioka: Immunology Frontier Research Center, Osaka University, Suita, Japan.
  14. Ritsuko Komine: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
  15. Chiaki Okura: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
  16. Masumi Shimizu: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
  17. Masahito Ikawa: Immunology Frontier Research Center, Osaka University, Suita, Japan. ORCID
  18. Akihiko Yoshimura: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
  19. Rimpei Morita: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan. rimpei-morita@nms.ac.jp.
  20. Lark Kyun Kim: Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. LKKIM@yuhs.ac. ORCID
PMID: 39179640 DOI: 10.1038/s41418-024-01367-6

Abstract

Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.

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Grants

  1. NRF-2023R1A2C1005804/National Research Foundation of Korea (NRF)
  2. RS-2024-00408822/National Research Foundation of Korea (NRF)
  3. NRF- 2022M3A9B6017424/National Research Foundation of Korea (NRF)
  4. 16H05178/MEXT | Japan Society for the Promotion of Science (JSPS)
  5. 22K07140/MEXT | Japan Society for the Promotion of Science (JSPS)

MeSH Term

Arthritis, Rheumatoid
NLR Family, Pyrin Domain-Containing 3 Protein
Animals
Gelsolin
Inflammasomes
Humans
Mice
Mice, Knockout
Mice, Inbred C57BL
Macrophages
Lipopolysaccharides
Male
Mitochondria

Chemicals

NLR Family, Pyrin Domain-Containing 3 Protein
Gelsolin
Inflammasomes
Lipopolysaccharides
NLRP3 protein, human
Nlrp3 protein, mouse
Journal Article
Article has an altmetric score of 1

Word Cloud

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