Abstract
Sepsis-induced acute lung injury (ALI) is prevalent in patients with sepsis and has a high mortality rate. Peptidyl arginine deiminase 2 (PADI2) and PADI4 play crucial roles in mediating the host’s immune response in sepsis, but their specific functions remain unclear. Our study shows that Padi2–/– Padi4–/– double KO (DKO) improved survival, reduced lung injury, and decreased bacterial load in Pseudomonas aeruginosa (PA) pneumonia–induced sepsis mice. Using single-cell RNA-Seq (scRNA-Seq), we found that the deletion of Padi2 and Padi4 reduced the Nlrp3+ proinflammatory macrophages and fostered Chil3+ myeloid cell differentiation into antiinflammatory macrophages. Additionally, we observed the regulatory role of the NLRP3/Ym1 axis upon DKO, confirmed by Chil3 knockdown and Nlrp3-KO experiments. Thus, eliminating Padi2 and Padi4 enhanced the polarization of Ym1+ M2 macrophages by suppressing NLRP3, aiding in inflammation resolution and lung tissue repair. This study unveils the PADIs/NLRP3/Ym1 pathway as a potential target in treatment of sepsis-induced ALI.
| Original language | English (US) |
|---|---|
| Article number | e181686 |
| Journal | JCI Insight |
| Volume | 9 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 22 2024 |
Funding
We express our gratitude to the MDRC MGC for generating the Padi2/Padi4-DKO mice. We are grateful to Gabriel Nunez for the generous provision of the Nlrp3-KO mice. We also thank the UMICH Immune Monitoring Shared Resource for ELISA service, the In-Vivo Animal Core for IHC service, and the Advanced Genomics Core for scRNA-Seq service. This work was supported by grants from the NIH R01 (grant no. R01HL155116) awarded to YL and the Joint Institute for Translational and Clinical Research (grant no. U068874) also awarded to YL.
ASJC Scopus subject areas
- General Medicine