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MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance
Yan Liu1, Feng Qi2, Hongrui Zeng1
1Department of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing, China.
Abstract:
Increasing evidence highlights the crucial role of endotoxin tolerance in the regulation of the sepsis, yet its underlying mechanisms remain poorly understood. Here, we provide evidence to support a novel role for the mitochondrial pyruvate carrier1 (MPC1)-mediated mitochondrial oxidative stress resistance in regulation of endotoxin tolerance in macrophages. We observed decrease expression of MPC1 in macrophages of sepsis models both in vitro and in vivo, while LPS-tolerant macrophages exhibited increased MPC1 levels. Overexpression of MPC1 significantly reduced LPS-induced inflammatory responses and oxidative stress, suggesting its anti-inflammatory properties. Intriguingly, we found that overexpression of MPC1 did not foster endotoxin tolerance in macrophages. Furthermore, Overexpression of MPC1 inhibited mitochondrial oxidative stress resistance mediated by mitochondrial reactive oxygen species (mtROS), which weakened the resistance of macrophages to LPS secondary stimulation, and then inhibited endotoxin tolerance. Despite mtROS typically acting as pro-inflammatory mediators, our findings indicate that mtROS which regulated via the SIRT3/SOD2 pathway, is essential for MPC1's control over mitochondrial oxidative stress resistance and endotoxin tolerance. Collectively, these findings uncover a novel mechanism through which MPC1 modulates inflammation and induces endotoxin tolerance, underscoring the potential of targeting MPC1 in sepsis treatment.
Insights
Mitochondrial pyruvate carrier 1 (MPC1) plays a key role in regulating endotoxin tolerance in macrophages. MPC1 influences mitochondrial oxidative stress resistance, impacting inflammatory responses and sepsis treatment potential.
Area of Science:
- Immunology
- Cell Biology
- Mitochondrial Biology
Background:
- Endotoxin tolerance is crucial for sepsis regulation, but its mechanisms are unclear.
- Macrophages play a central role in the immune response to sepsis.
Purpose of the Study:
- To investigate the role of mitochondrial pyruvate carrier 1 (MPC1) in regulating endotoxin tolerance in macrophages.
- To elucidate the mechanisms by which MPC1 influences inflammatory responses and oxidative stress.
Main Methods:
- Studied MPC1 expression in macrophages from in vitro and in vivo sepsis models.
- Manipulated MPC1 levels (overexpression) to assess its impact on inflammatory responses and oxidative stress.
- Investigated the role of mitochondrial reactive oxygen species (mtROS) and the SIRT3/SOD2 pathway.
Main Results:
- MPC1 expression decreased in sepsis models but increased in LPS-tolerant macrophages.
- MPC1 overexpression reduced LPS-induced inflammation and oxidative stress, but impaired endotoxin tolerance.
- MPC1 inhibited mtROS-mediated mitochondrial oxidative stress resistance, weakening macrophage tolerance to secondary LPS stimulation.
- mtROS, regulated by SIRT3/SOD2, is essential for MPC1's control over mitochondrial oxidative stress resistance and endotoxin tolerance.
Conclusions:
- MPC1 is a novel regulator of inflammation and endotoxin tolerance in macrophages.
- MPC1 modulates mitochondrial oxidative stress resistance through mtROS, impacting sepsis progression.
- Targeting MPC1 presents a potential therapeutic strategy for sepsis treatment.
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