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Acacetin Attenuates Sepsis-induced Acute Lung Injury via NLRC3-NF-κB Pathway

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Abstract

Acacetin, a flavonoid derived compound has been recognized for its diverse biological activities, such as anti-oxidative and anti-inflammatory effects. Acute lung injury (ALI) is a severe condition characterized by respiratory insufficiency and tissue damage, commonly triggered by pneumonia and severe sepsis. These conditions induce an inflammatory response via Toll-like receptor 4 (TLR4) signaling activation. This study explored acacetin's therapeutic potential against lipopolysaccharide (LPS) induced ALI in mice, focusing on its ability to modulate the NF-κB pathway via regulation of the Nod-like receptor family CARD domain containing 3 (NLRC3), a signal sensor that plays an important role in the regulation of inflammation and the maintenance of homeostasis. Our findings revealed that high-dose acacetin reduced the mortality rate of ALI mice, significantly ameliorated LPS-induced lung pathological changes, reduced lung edema, and decreased the expression of inflammatory mediators in lung tissues. This protective impact of acacetin appears to stem form its capacity to enhance NLRC3 expression, which, intern, can inhibit the activation of NF-κB and subsequently inhibit the production of inflammatory mediators. NLRC3 deficiency inhibits the protective effect of acacetin on ALI mice. Molecular docking also verified that acacetin tightly bound acacetin to NLRC3. Additionally, acacetin was found to influence macrophage recruitment dynamics via NLRC3, inhibiting the overactivation of NLRC3-NF-κB related pathways. Taken together, our results indicate that acacetin inhibited LPS-induced acute lung injury and macrophage overrecruitment to the lungs in mice by upregulating NLRC3.

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 No datasets were generated or analysed during the current study.

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Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81770056, 81971563, 82272330) and Key Research and Development Project of Shaanxi province (2023-YBSF-405).

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Author notes

  1. Yingchou Xiao and Bo Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, 710000, China

    Yingchou Xiao, Bo Zhang & Ying Luo

  2. Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, 710000, China

    Shiyuan Hou, Xing Shen, Xingan Wu, Rongrong Liu & Ying Luo

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  1. Yingchou Xiao
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Contributions

Y.C.X and B.Z wrote the main manuscript text, S.Y.H, X.S and R.R.L prepared Figs. 1–9. ALL authors reviewed the manuscript.

Corresponding authors

Correspondence to Xingan Wu, Rongrong Liu or Ying Luo.

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Ethics Statement

The experimental procedures was approved by the Institutional Animal Ethics and Use Committee of the Fourth Military Medical University.

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Xiao, Y., Zhang, B., Hou, S. et al. Acacetin Attenuates Sepsis-induced Acute Lung Injury via NLRC3-NF-κB Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-02040-3

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