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Taraxerone inhibits M1 polarization and alleviates sepsis-induced acute lung injury by activating SIRT1
Lang Deng1, Weixi Xie1, Miao Lin1
1Xiangya Nursing School, Central South University, Changsha, 410013, Hunan, China.
Background:
Acute lung injury (ALI) is the most lethal disease associated with sepsis, and there is a lack of effective drug treatment. As the major cells of sepsis-induced ALI, macrophages polarize toward the proinflammatory M1 phenotype and secrete multiple inflammatory cytokines to accelerate the disease process through nuclear factor kappa-B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways. Taraxerone, the main component of the Chinese medicinal Sedum, possesses numerous biological activities. However, uncertainty remains regarding the potential of taraxerone to protect against sepsis-induced ALI. This study aimed to investigate the effects and mechanisms of taraxerone against ALI.
Methods:
An animal model for ALI was established by cecal ligation and puncture and treated with taraxerone via intraperitoneal administration. The protective effect of taraxerone on the lungs was analyzed using H&E staining, dihydroethidium staining, ELISA kits, cell counting, myeloperoxidase kit, malondialdehyde kit, glutathione kit, superoxide dismutase kit and flow cytometry. Western blotting, RT-PCR, flow cytometry, co-immunoprecipitation, and immunofluorescence were used to investigate the regulatory of taraxerone on SIRT1.
Results:
Our study demonstrates for the first time that taraxerone can activate SIRT1 in macrophages, promoting SIRT1 activity. This activation inhibited the NF-κB signaling pathway primarily through the dephosphorylation and deacetylation of p65. Simultaneously, taraxerone disrupted the NLRP3 inflammasome signaling pathway, thereby alleviating M1 polarization of macrophages and mitigating sepsis-induced pulmonary inflammation and oxidative stress. In vivo, EX527 was used to validate the anti-inflammatory and anti-oxidative stress effects of taraxerone mediated by SIRT1.
Conclusion:
SIRT1-mediated anti-inflammatory and anti-oxidative stress effects may be important targets for taraxerone in treating ALI.
Insights
Taraxerone activates SIRT1 in macrophages, reducing inflammation and oxidative stress in sepsis-induced acute lung injury (ALI). This natural compound offers a potential therapeutic strategy for ALI by inhibiting key inflammatory pathways.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Sepsis-induced acute lung injury (ALI) is a critical condition with limited therapeutic options.
- Macrophages play a key role in ALI pathogenesis, polarizing to a pro-inflammatory M1 phenotype.
- Taraxerone, a compound from Sedum, is explored for its potential protective effects against ALI.
Purpose of the Study:
- To investigate the therapeutic effects of taraxerone on sepsis-induced ALI.
- To elucidate the underlying molecular mechanisms of taraxerone's action, focusing on SIRT1 activation.
Main Methods:
- Establishment of a murine ALI model using cecal ligation and puncture.
- Administration of taraxerone and assessment of lung injury via histological and biochemical analyses.
- Investigation of taraxerone's impact on SIRT1, NF-κB, and NLRP3 inflammasome pathways using molecular biology techniques.
Main Results:
- Taraxerone activates SIRT1 in macrophages, enhancing its activity.
- SIRT1 activation by taraxerone inhibited NF-κB and NLRP3 inflammasome signaling pathways.
- Taraxerone treatment alleviated M1 macrophage polarization, pulmonary inflammation, and oxidative stress in ALI models.
Conclusions:
- Taraxerone exhibits protective effects against sepsis-induced ALI.
- SIRT1 activation is a key mechanism mediating taraxerone's anti-inflammatory and anti-oxidative effects.
- Taraxerone represents a promising therapeutic agent for ALI targeting SIRT1.
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