GDF15 attenuates sepsis-associated liver injury by regulating macrophage polarization via the AMPK/PKM2/HIF-1a
Li Wang1, XianDong Kuang1, Huan Li1
1Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Abstract:
Sepsis-associated liver injury (SALI) is a common and severe complication of sepsis, and effective clinical treatment strategies are still lacking. Macrophages, a highly heterogeneous population of immune cells, play a key role in triggering and regulating the cytokine storm. Enhanced glycolysis is the key driver behind the increased proportion of M1 macrophages and the elevated release of pro-inflammatory factors. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine with anti-inflammatory and tissue repair functions. However, the specific role and mechanism of GDF15 in SALI remain unclear. In this study, a mouse SALI model and a macrophage M1 polarization model were established using lipopolysaccharide (LPS). Recombinant GDF15 protein was used to investigate its role and related mechanisms. The results showed that GDF15 markedly alleviated liver injury and effectively suppressed the release of pro-inflammatory cytokines. In both in vivo and in vitro experiments, GDF15 promoted the polarization of macrophages from the M1 to the M2 phenotype. Mechanistically, GDF15 inhibits the pyruvate kinase M2 (PKM2)/hypoxia inducible factor 1α (HIF-1α) axis-mediated glycolysis and macrophage M1 polarization by activating AMP-activated protein kinase (AMPK). These findings indicate that GDF15 is a potential target for the clinical prevention and treatment of SALI.
Insights
Growth differentiation factor 15 (GDF15) can treat sepsis-associated liver injury (SALI) by reducing inflammation. GDF15 promotes macrophage M2 polarization, inhibiting M1-driven cytokine storms and liver damage.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Sepsis-associated liver injury (SALI) is a severe complication with limited treatments.
- Macrophages, particularly M1 phenotype, drive inflammation and cytokine storms in sepsis.
- Enhanced glycolysis fuels M1 macrophage polarization and pro-inflammatory factor release.
Purpose of the Study:
- To investigate the role and mechanism of Growth Differentiation Factor 15 (GDF15) in sepsis-associated liver injury (SALI).
- To explore GDF15's potential as a therapeutic target for SALI.
Main Methods:
- Established mouse models of SALI and M1 macrophage polarization using lipopolysaccharide (LPS).
- Utilized recombinant GDF15 protein for in vivo and in vitro experiments.
- Investigated the effects of GDF15 on macrophage polarization, cytokine release, and glycolysis.
Main Results:
- GDF15 significantly alleviated liver injury and suppressed pro-inflammatory cytokine release in SALI models.
- GDF15 promoted the M1 to M2 macrophage polarization shift.
- GDF15 inhibited glycolysis and M1 polarization by activating AMP-activated protein kinase (AMPK), targeting the PKM2/HIF-1α axis.
Conclusions:
- GDF15 demonstrates therapeutic potential for sepsis-associated liver injury.
- GDF15 exerts anti-inflammatory effects by modulating macrophage polarization and glycolysis.
- Targeting GDF15 offers a promising strategy for clinical SALI treatment.
