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Sestrin2 induction contributes to anti-inflammatory responses and cell survival by globular adiponectin in macrophages

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Abstract

Adiponectin, an adipose tissue-derived hormone, exhibits a modulatory effect on cell death/survival and possesses potent anti-inflammatory properties. However, the underlying molecular mechanisms remain elusive. Sestrin2, a stress-inducible metabolic protein, has shown cytoprotective and inflammation-modulatory effects under stressful conditions. In this study, we examined the role of sestrin2 signaling in the modulation of cell survival and inflammatory responses by globular adiponectin (gAcrp) in macrophages. We observed that gAcrp induced a significant increase in sestrin2 expression in both RAW 264.7 murine macrophages and primary murine macrophages. Notably, gAcrp treatment markedly increased expression of hypoxia inducible factor-1 α (HIF-1α) and gene silencing of HIF-1α blocked sestrin2 induction by gAcrp. In addition, pretreatment with a pharmacological inhibitor of ERK or PI3K abrogated both sestrin2 and HIF-1α expression by gAcrp, indicating that ERK/PI3K-mediated HIF-1α signaling pathway plays a critical role in sestrin2 induction by gAcrp. Furthermore, sestrin2 induction is implicated in autophagy activation, and knockdown of sestrin2 prevented enhanced cell viability by gAcrp. Moreover, gene silencing of sestrin2 caused restoration of gAcrp-induced expression of anti-inflammatory genes in a gene-selective manner. Taken together, these results indicate that sestrin2 induction critically contributes to cell survival and anti-inflammatory responses by gAcrp in macrophages.

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Acknowledgements

This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2021R1A2C1013132) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1A6A1A03044512). The authors thank the Core Research Support Center for Natural Products and Medical Materials (CRCNM) for the technical support regarding the confocal microscopic analysis.

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  1. Sumin Lee and Duc-Vinh Pham have contributed equally to this work.

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  1. College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea

    Sumin Lee, Duc-Vinh Pham & Pil-Hoon Park

  2. Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Republic of Korea

    Pil-Hoon Park

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  1. Sumin Lee
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PHP; designed the study. SL and DP; performed the experiments. PHP, SL, and DP; analyzed the data. PHP and SL; wrote the manuscript.

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Correspondence to Pil-Hoon Park.

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Lee, S., Pham, DV. & Park, PH. Sestrin2 induction contributes to anti-inflammatory responses and cell survival by globular adiponectin in macrophages. Arch. Pharm. Res. 45, 38–50 (2022). https://doi.org/10.1007/s12272-021-01364-0

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