Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages.

Sepsis-induced acute lung injury (ALI) is prevalent in septic patients and has a high mortality rate. Peptidyl arginine deiminase (PADI) 2 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 knockout (DKO) improved survival, reduced lung injury, decreased bacterial load in Pseudomonas aeruginosa (PA) pneumonia-induced sepsis mice. Using single-cell RNA sequencing (scRNA-seq), we found that the deletion of Padi2 and Padi4 reduced the Nlrp3+ pro-inflammatory macrophages and fostered Chil3+ myeloid cell differentiation into anti-inflammatory macrophages. Additionally, we observed the regulatory role of NLRP3-Ym1 axis upon DKO, confirmed by Chil3 knockdown and Nlrp3 KO experiments. Thus, eliminating Padi2 and Padi4 enhances the polarization of Ym1+ M2 macrophages by suppressing NLRP3, aiding in inflammation resolution and lung tissue repair. study unveils the PADI2/PADI4-NLRP3-Ym1 pathway as a potential target in treatment of sepsis-induced ALI.