A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation

Ji Won Lee, Leah Eunjung Kim, Hyun Jung Shim, Eun Kyoung Kim, Won Chan Hwang, Do Sik Min, Seong Woon Yu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Ro5-4864 and PK11195, prototypical synthetic ligands of translocator protein 18 kDa (TSPO), have shown anti-inflammatory effects in several models of inflammatory diseases; however, their biochemical mechanisms remain poorly understood. Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation as a part of the innate immune system, has been implicated in a variety of inflammatory diseases. Here, we demonstrate for the first time that TSPO ligands, especially Ro5-4864, potently suppressed ATP-induced NLRP3 inflammasome activation in THP-1 and BMDM cells. Detailed action mechanism was further investigated in THP-1 cells. Ro5-4864 efficiently attenuated NLRP3 translocation to mitochondria, inflammasome assembly/oligomerization, activation of caspase-1, and subsequent secretion of the mature forms of interleukin-1β and -18. Ro5-4864 also reduced the production of mitochondrial superoxide and preserved the mitochondrial membrane potential in ATP-treated cells, suggesting that Ro5-4864 may act on mitochondria or more upstream targets in NLRP3 inflammasome signaling. We also observed the distinct effects of the TSPO ligands between THP-1 monocytes and macrophages, which suggested different NLRP3 inflammasome signaling depending on cell type. Collectively, our novel findings demonstrate that Ro5-4864 effectively inhibited ATP-induced NLRP3 inflammasome activation through the prevention of mitochondrial perturbation. Our results indicate Ro5-4864 as a promising candidate for the treatment of NLRP3 inflammasome-related diseases.

Original languageEnglish
Pages (from-to)587-593
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume474
Issue number3
DOIs
Publication statusPublished - 2016 Jun 3

Fingerprint

Inflammasomes
Adenosine Triphosphate
Chemical activation
Ligands
Proteins
Mitochondria
Caspase 1
Oligomerization
Interleukin-18
Mitochondrial Membrane Potential
Macrophages
Immune system
4'-chlorodiazepam
Pyrin Domain
Interleukin-1
Superoxides
Monocytes
Immune System
Anti-Inflammatory Agents
Cells

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lee, Ji Won ; Kim, Leah Eunjung ; Shim, Hyun Jung ; Kim, Eun Kyoung ; Hwang, Won Chan ; Min, Do Sik ; Yu, Seong Woon. / A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation. In: Biochemical and Biophysical Research Communications. 2016 ; Vol. 474, No. 3. pp. 587-593.
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A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation. / Lee, Ji Won; Kim, Leah Eunjung; Shim, Hyun Jung; Kim, Eun Kyoung; Hwang, Won Chan; Min, Do Sik; Yu, Seong Woon.

In: Biochemical and Biophysical Research Communications, Vol. 474, No. 3, 03.06.2016, p. 587-593.

Research output: Contribution to journalArticle

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