IL-35 alleviates ferroptosis in macrophage by activating the NRF2/GPX4 pathway to improve sepsis-induced ARDS
Panting Liu1, Chen Zhang1, Minkang Guo2
1Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Disease, Chongqing, China.
Objective:
Macrophage M1/M2 polarization is essential to mitigate acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Ferroptosis is pivotal in sepsis-induced ALI and interleukin (IL)-35 has been reported to exert anti-inflammatory effects. Therefore, we aimed to investigate the effect of IL-35 on ferroptosis and macrophage polarization in ARDS.
Methods:
We constructed an in vitro inflammation model using lipopolysaccharide (LPS) to assess the macrophage polarization, ferroptosis, phagocytosis, and killing effects after IL-35 treatment. A cecal ligation and puncture model was established, and lung injury, ferroptosis, and macrophage polarization were detected following rIL-35 treatment. The indexes showed changes after the use of an NRF2 inhibitor. Additionally, we quantified the injury and apoptosis of MLE-12 cells after co-culture with RAW264.7 cells and detected IL-10 expression.
Results:
IL-35 blocked LPS-induced polarization of RAW264.7 and bone marrow-derived macrophages to M1 and promoted M2 generation. It up-regulated the NRF2/GPX4 pathway and attenuated ferroptosis in macrophages. When NRF2 was inhibited, the regulatory effects of IL-35 on the macrophage phenotype and ferroptosis were reversed. After co-culture with IL-35-treated RAW264.7, the apoptosis of MLE-12 cells was reduced and IL-10 expression was increased.
Conclusion:
IL-35 alleviates ALI by reducing macrophage ferroptosis and attenuating the activation of proinflammatory macrophages via the NRF2/GPX4 pathway. IL-35-induced macrophages phenotypic remodeling reduce the apoptosis of lung epithelial cells by secreting IL-10.
Insights
Interleukin-35 (IL-35) alleviates acute lung injury (ALI) by reducing macrophage ferroptosis and inflammation. IL-35 promotes M2 macrophage polarization and protects lung epithelial cells from apoptosis.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Macrophage polarization (M1/M2) is crucial for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
- Ferroptosis plays a key role in sepsis-induced ALI.
- Interleukin-35 (IL-35) exhibits anti-inflammatory properties.
Purpose of the Study:
- To investigate the effects of IL-35 on ferroptosis and macrophage polarization in ARDS.
- To elucidate the underlying molecular mechanisms involving the NRF2/GPX4 pathway.
Main Methods:
- In vitro inflammation model (LPS) and in vivo cecal ligation and puncture model were used.
- Macrophage polarization, ferroptosis, and lung injury were assessed.
- NRF2 inhibition and MLE-12 cell apoptosis were quantified.
Main Results:
- IL-35 inhibited M1 polarization and promoted M2 polarization of macrophages.
- IL-35 upregulated the NRF2/GPX4 pathway, attenuating macrophage ferroptosis.
- IL-35 reduced MLE-12 cell apoptosis and increased IL-10 expression.
Conclusions:
- IL-35 alleviates ALI by reducing macrophage ferroptosis and pro-inflammatory macrophage activation via the NRF2/GPX4 pathway.
- IL-35-induced macrophage remodeling reduces lung epithelial cell apoptosis through IL-10 secretion.
