IL-27 Aggravates Sepsis-Induced ARDS by Driving Macrophage Ferroptosis Through Activation of NCOA4-Mediated
Minkang Guo1,2, Meng Xiong1, Jindian Shi1
1Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Background:
Acute respiratory distress syndrome (ARDS) induced by sepsis is a clinical syndrome characterized by high morbidity and mortality rates. This study aims to clarify the effects of recombinant mouse IL-27 protein on macrophage ferritinophagy, macrophage polarization, and its interventional role in sepsis-induced ARDS.
Methods:
This study utilized wild-type (WT) and IL-27 receptor knockout (IL-27R-/-) mice to establish a cecal ligation and puncture (CLP)-induced sepsis model. The post-modeling mice were randomly divided into four groups: control group, CLP model group, IL-27 combined with CLP treatment group, and IL-27+CLP+PROTAC NCOA4 degrader-1 (Compound V3, CV3) combined treatment group. For the in vitro experiments using RAW 264.7 cells and Bone Marrow-Derived Macrophages (BMDMs), the cells were divided into four main groups as follows: the control group, the lipopolysaccharide (LPS) model group, the LPS+IL-27 treatment group, and the LPS+IL-27+CV3 combination treatment group.
Results:
This study investigates the role of IL-27 in exacerbating ferritinophagy and ferroptosis in macrophages and septic lung injury, and explores the therapeutic potential of the NCOA4 degrader CV3. We found that IL-27 synergizes with LPS to enhance NCOA4-mediated ferritinophagy, leading to increased degradation of FTH1, upregulation of LC3A/B, and promotion of ferroptosis. Ferritinophagy amplification drove M1 macrophage polarization and inflammatory cytokine release. CV3, a PROTAC-based NCOA4 degrader, effectively disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy, and mitigated ferroptosis and inflammation. In murine models of sepsis-induced ARDS, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis. Notably, IL-27R-/- mice were resistant to IL-27-induced exacerbation of ferritinophagy and lung injury, confirming the specificity of IL-27 signaling.
Conclusion:
These findings reveal a potential mechanistic link between NCOA4-mediated ferritinophagy and sepsis-associated ARDS pathogenesis. Targeting this pathway with CV3 may offer a novel therapeutic strategy, which warrants further investigation.
Insights
Interleukin-27 (IL-27) worsens sepsis-induced acute respiratory distress syndrome (ARDS) by promoting macrophage ferritinophagy. A novel NCOA4 degrader, CV3, effectively reverses this process, offering a potential therapeutic strategy for ARDS.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe condition with high mortality.
- Understanding the molecular mechanisms underlying ARDS is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of recombinant mouse IL-27 protein in macrophage ferritinophagy and polarization in sepsis-induced ARDS.
- To explore the therapeutic potential of a PROTAC NCOA4 degrader (CV3) in mitigating sepsis-induced ARDS.
Main Methods:
- Established a cecal ligation and puncture (CLP)-induced sepsis model in wild-type and IL-27 receptor knockout (IL-27R-/-) mice.
- Utilized in vitro experiments with RAW 264.7 cells and bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS) and/or IL-27 and CV3.
- Assessed macrophage polarization, ferritinophagy, ferroptosis, and inflammatory cytokine release.
Main Results:
- IL-27 synergized with LPS to enhance NCOA4-mediated ferritinophagy, leading to ferroptosis and M1 macrophage polarization.
- CV3 disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy and ferroptosis, and reduced inflammation.
- In vivo, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis in a murine sepsis-ARDS model.
- IL-27R-/- mice showed resistance to IL-27-induced exacerbation of lung injury.
Conclusions:
- IL-27 exacerbates sepsis-induced ARDS by promoting NCOA4-mediated ferritinophagy and ferroptosis in macrophages.
- The NCOA4 degrader CV3 demonstrates therapeutic potential by inhibiting ferritinophagy and mitigating lung injury.
- Targeting the NCOA4-ferritinophagy pathway presents a novel therapeutic strategy for sepsis-associated ARDS.
