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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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NRF2 activation by 2-methoxycinnamaldehyde attenuates inflammatory responses in macrophages via enhancing autophagy flux

  • Kim, Bo-Sung (Department of Korean Medical Science, School of Korean Medicine, Pusan National University) ;
  • Shin, Minwook (RNA Therapeutics Institute, University of Massachusetts Chan Medical School) ;
  • Kim, Kyu-Won (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Ha, Ki-Tae (Department of Korean Medical Science, School of Korean Medicine, Pusan National University) ;
  • Bae, Sung-Jin (Department of Molecular Biology and Immunology, Kosin University College of Medicine)
  • Received : 2022.04.11
  • Accepted : 2022.06.15
  • Published : 2022.08.31
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Abstract

A well-controlled inflammatory response is crucial for the recovery from injury and maintenance of tissue homeostasis. The anti-inflammatory response of 2-methoxycinnamaldehyde (2-MCA), a natural compound derived from cinnamon, has been studied; however, the underlying mechanism on macrophage has not been fully elucidated. In this study, LPS-stimulated production of TNF-α and NO was reduced by 2-MCA in macrophages. 2-MCA significantly activated the NRF2 pathway, and expression levels of autophagy-associated proteins in macrophages, including LC3 and P62, were enhanced via NRF2 activation regardless of LPS treatment, suggesting the occurrence of 2-MCA-mediated autophagy. Moreover, evaluation of autophagy flux using luciferase-conjugated LC3 revealed that incremental LC3 and P62 levels are coupled to enhanced autophagy flux. Finally, reduced expression levels of TNF-α and NOS2 by 2-MCA were reversed by autophagy inhibitors, such as bafilomycin A1 and NH4Cl, in LPS-stimulated macrophages. In conclusion, 2-MCA enhances autophagy flux in macrophages via NRF2 activation and consequently reduces LPS-induced inflammation.

Keywords

Acknowledgement

M.S., S.-J.B. and K.-W.K. conceived and designed the research. M.S. and B.-S.K. performed the experiments and collected the data. B.-S.K. and S.-J.B. wrote the manuscript. M.S., K.-W.K. and K.-T.H. analyzed the data and revised the manuscript. K.-T.H. and S.-J.B. provided guidance on the study and supervised the project. All the authors reviewed the manuscript and agreed to the submission. This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MIST; NRF-2021R1A2B5B01002223 to Kyu-Won Kim, NRF-2020R1C1C1003703 to Sung-Jin Bae, and NRF-2021R1A4A1025662 to Sung-Jin Bae and Ki-Tae Ha).

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