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NRF2 activation by 2-methoxycinnamaldehyde attenuates inflammatory responses in macrophages via enhancing autophagy flux.

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. [BMB Reports 2022; 55(8): 407-412].

SUBMITTER: Kim BS

PROVIDER: S-EPMC9442350 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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NRF2 activation by 2-methoxycinnamaldehyde attenuates inflammatory responses in macrophages via enhancing autophagy flux.

Kim Bo-Sung BS Shin Minwook M Kim Kyu-Won KW Ha Ki-Tae KT Bae Sung-Jin SJ

BMB reports 20220801 8

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 autophag ...[more]

PMID: 35725014

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Project description:Previous studies have revealed the anti-inflammatory properties of rice bran oil (RBO), but the detailed mechanisms are poorly understood. Recent studies on the molecular/cellular anti-inflammatory mechanisms of dietary components have demonstrated that mitochondrial respiration plays a key role in macrophage functioning. Since dietary lipids are major substrates for mitochondrial respiration through ?-oxidation, the current study examined whether RBO regulates inflammatory responses by modulating mitochondrial energy metabolism. Palm oil (PO), enriched with palmitic acid which are known to be effectively taken up by cells and used for oxidative phosphorylation, served as a positive control. In the in vitro model of LPS-stimulated RAW 264.7 murine cells, the levels of pro-inflammatory cytokines (IL-6 and TNF-?) in the culture supernatant were significantly reduced by RBO treatment. In contrast, secretion of the anti-inflammatory cytokine IL-10 was upregulated by RBO. Transcription of genes encoding inflammatory mediator molecules (COX-2 and iNOS) and expression of activation markers (CD80, CD86, and MHC-II) in LPS-stimulated RAW 264.7 cells were suppressed by RBO. Mitochondrial respiration (as assessed by an extracellular flux analyzer) increased upon RBO treatment, as the basal respiration, maximal respiration, ATP production, and spare respiratory capacity were upregulated. In an in vivo study, C57BL/6 mice were fed a negative control diet containing corn oil (CO), PO, or RBO for 4 weeks, and bone marrow-derived macrophages (BMDM) were isolated from their tibias and femurs. In pro-inflammatory M1-polarized BMDM (M1-BMDM), the RBO-induced suppression of IL-6 and TNF-? was recapitulated in vivo. Mitochondrial respiration in M1-BMDM also increased following the RBO intervention and the PO control treatment as compared to CO fed negative control. Overall, the current study for the first time demonstrates that RBO regulates inflammatory responses in murine macrophages by upregulating mitochondrial respiration. Further clinical studies are required to validate the animal study.

Dataset Information

NRF2 activation by 2-methoxycinnamaldehyde attenuates inflammatory responses in macrophages via enhancing autophagy flux.

Publications

NRF2 activation by 2-methoxycinnamaldehyde attenuates inflammatory responses in macrophages via enhancing autophagy flux.

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