2022年 新着論文 26 炎症生物学分野から論文が発表されました

Oridonin suppresses particulate-induced NLRP3-independent IL-1α release to prevent crystallopathy in the lung

Int Immunol. 2022 Sep 9;34(10):493-504. doi: 10.1093/intimm/dxac018.

Authors

Kenta Ikoma  1 Michihiro Takahama  2   3 Atsushi Kimishima  4 Yixi Pan  1 Manabu Taura  1 Akiyoshi Nakayama  2   5 Masayoshi Arai  4 Naoki Takemura  1 Tatsuya Saitoh  1   2   6

Affiliations

  • 1 Laboratory of Bioresponse Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
  • 2 Division of Inflammation Biology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
  • 3 Pritzker School of Molecular Engineering, the University of Chicago, Chicago, IL, USA.
  • 4 Laboratory of Natural Products for Drug Discovery, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
  • 5 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, Japan.
  • 6 Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan.

Abstract

The human body is exposed to various particulates of industrial, environmental, or endogenous origin. Invading or intrinsic particulates can induce inflammation by aberrantly activating the immune system, thereby causing crystallopathies. When immune cells such as macrophages phagocytose the particulates, their phagolysosomal membranes undergo mechanical damage, eventually leading to pyroptotic cell death accompanied by the release of inflammatory cytokines, including interleukin (IL)-1α and IL-1β. The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is responsible for particulate-induced IL-1β release and is therefore regarded as a potential therapeutic target for inflammation-mediated crystallopathies. However, IL-1α is released after particulate stimulation in an NLRP3 inflammasome-independent manner and plays a critical role in disease development. Therefore, drugs that exert potent anti-inflammatory effects by comprehensively suppressing particulate-induced responses, including IL-1β release and IL-1α release, should be developed. Here, we found that oridonin, a diterpenoid isolated from Isodon japonicus HARA, strongly suppressed particulate-induced cell death, accompanied by the release of IL-1α and IL-1β in mouse and human macrophages. Oridonin reduced particulate-induced phagolysosomal membrane damage in macrophages without affecting phagocytosis of particulates. Furthermore, oridonin treatment markedly suppressed the symptoms of silica particle-induced pneumonia, which was attributed to the release of IL-1α independently of NLRP3. Thus, oridonin is a potential lead compound for developing effective therapeutics for crystallopathies attributed to NLRP3-dependent as well as NLRP3-independent inflammation.

Keywords: cytokine; inflammation; innate immunity; organelle; silicosis.

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