Journal
ARCHIVES OF PHARMACAL RESEARCH
Volume 45, Issue 1, Pages 38-50Publisher
PHARMACEUTICAL SOC KOREA
DOI: 10.1007/s12272-021-01364-0
Keywords
Adiponectin; Cell survival; Inflammation; Sestrin2
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Funding
- Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2021R1A2C1013132]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2020R1A6A1A03044512]
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The study demonstrates that in macrophages, globular adiponectin modulates cell survival and anti-inflammatory responses by activating the sestrin2 signaling pathway. The induction of sestrin2 is crucial for autophagy activation and enhanced cell viability by adiponectin.
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 alpha (HIF-1 alpha) and gene silencing of HIF-1 alpha blocked sestrin2 induction by gAcrp. In addition, pretreatment with a pharmacological inhibitor of ERK or PI3K abrogated both sestrin2 and HIF-1 alpha expression by gAcrp, indicating that ERK/PI3K-mediated HIF-1 alpha 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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