NRF2 activation by 2-methoxycinnamaldehyde attenuates inflammatory responses in macrophages via enhancing autophagy flux
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A well-controlled inflammatory response is crucial for the recoveryfrom injury and maintenance of tissue homeostasis. Theanti-inflammatory response of 2-methoxycinnamaldehyde (2-MCA),a natural compound derived from cinnamon, has been studied;however, the underlying mechanism on macrophage has notbeen fully elucidated. In this study, LPS-stimulated productionof TNF-α and NO was reduced by 2-MCA in macrophages. 2-MCA significantly activated the NRF2 pathway, and expressionlevels of autophagy-associated proteins in macrophages, includingLC3 and P62, were enhanced via NRF2 activation regardlessof LPS treatment, suggesting the occurrence of 2-MCA-mediatedautophagy. Moreover, evaluation of autophagy flux usingluciferase-conjugated LC3 revealed that incremental LC3 andP62 levels are coupled to enhanced autophagy flux. Finally, reducedexpression levels of TNF-α and NOS2 by 2-MCA werereversed by autophagy inhibitors, such as bafilomycin A1 andNH4Cl, in LPS-stimulated macrophages. In conclusion, 2-MCAenhances autophagy flux in macrophages via NRF2 activationand consequently reduces LPS-induced inflammation.
Abstract
A well-controlled inflammatory response is crucial for the recoveryfrom injury and maintenance of tissue homeostasis. Theanti-inflammatory response of 2-methoxycinnamaldehyde (2-MCA),a natural compound derived from cinnamon, has been studied;however, the underlying mechanism on macrophage has notbeen fully elucidated. In this study, LPS-stimulated productionof TNF-α and NO was reduced by 2-MCA in macrophages. 2-MCA significantly activated the NRF2 pathway, and expressionlevels of autophagy-associated proteins in macrophages, includingLC3 and P62, were enhanced via NRF2 activation regardlessof LPS treatment, suggesting the occurrence of 2-MCA-mediatedautophagy. Moreover, evaluation of autophagy flux usingluciferase-conjugated LC3 revealed that incremental LC3 andP62 levels are coupled to enhanced autophagy flux. Finally, reducedexpression levels of TNF-α and NOS2 by 2-MCA werereversed by autophagy inhibitors, such as bafilomycin A1 andNH4Cl, in LPS-stimulated macrophages. In conclusion, 2-MCAenhances autophagy flux in macrophages via NRF2 activationand consequently reduces LPS-induced inflammation.
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