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Published on: December 18, 2010
BMAL1 deficiency in macrophages exacerbates sepsis-induced inflammatory response and organ damage by regulating
Xinjian Li1, Feng Qi2, Bin Yao1
1Department of General Surgery, Yingtan People's Hospital Yingtan, Jiangxi, China.
Abstract:
BMAL1 is a core gene involved in the regulation of circadian rhythm; however, its role in sepsis remains incompletely understood. In this study, we investigated the molecular mechanisms by which BMAL1 influences sepsis. Sepsis models were established both in vivo using C57BL/6J mice and in vitro using THP-1-derived macrophages. We observed a significant downregulation of BMAL1 expression in peritoneal macrophages and hepatic Kupffer cells during sepsis. Overexpression of BMAL1 in macrophages via plasmid transfection suppressed LPS-induced inflammatory responses and promoted M2 macrophage polarization. Conversely, administration of STL1267, a BMAL1 inhibitor, reduced BMAL1 expression in mice and further exacerbated systemic inflammation and multi-organ injury. Moreover, we identified PGC-1α as a key downstream effector of BMAL1. Knockdown of PGC-1α using short hairpin RNA (shRNA) abrogated BMAL1-mediated anti-inflammatory effects. Collectively, these findings uncover a novel mechanism by which BMAL1 regulates acute inflammatory responses and organ damage in sepsis, highlighting its potential as a therapeutic target.
Insights
The study reveals that BMAL1 (Brain and Muscle ARNT-Like 1) suppresses inflammation and organ damage in sepsis. Lower BMAL1 levels worsen sepsis, while boosting it offers therapeutic potential.
Area of Science:
- Molecular Biology
- Immunology
- Chronobiology
Background:
- Circadian rhythm gene BMAL1's role in sepsis is not fully understood.
- Sepsis involves complex inflammatory responses and organ damage.
Purpose of the Study:
- To investigate the molecular mechanisms of BMAL1 in sepsis.
- To explore BMAL1's influence on inflammatory responses and organ injury.
Main Methods:
- Established in vivo (mice) and in vitro (macrophages) sepsis models.
- Analyzed BMAL1 expression levels.
- Manipulated BMAL1 expression (overexpression and inhibition).
- Investigated downstream effector PGC-1α.
Main Results:
- BMAL1 expression was significantly downregulated in macrophages and Kupffer cells during sepsis.
- BMAL1 overexpression suppressed inflammation and promoted M2 macrophage polarization.
- BMAL1 inhibition exacerbated sepsis-induced inflammation and organ injury.
- PGC-1α was identified as a key downstream mediator of BMAL1's anti-inflammatory effects.
Conclusions:
- BMAL1 plays a protective role in sepsis by regulating inflammatory responses.
- BMAL1, via PGC-1α, mitigates acute inflammation and organ damage in sepsis.
- BMAL1 emerges as a potential therapeutic target for sepsis treatment.
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