한빛사논문
Jiyeon Lee 1, Fumiyuki Sasaki 2, Eri Koike 2, Minjeong Cho 1, Yeongun Lee 1, So Hee Dho 1, Jina Lee 1, Eunji Lee 1, Eri Toyohara 2, Mika Sunakawa 2, Mariko Ishibashi 2, Huynh Hiep Hung 2, Saki Nishioka 3, Ritsuko Komine 4, Chiaki Okura 4, Masumi Shimizu 2, Masahito Ikawa 3, Akihiko Yoshimura 4, Rimpei Morita 2,* and Lark Kyun Kim 1,*
1Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
2Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
3Immunology Frontier Research Center, Osaka University, Suita, Japan.
4Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
*Corresponding authors: correspondence to Rimpei Morita or Lark Kyun Kim
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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