Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury

• DOI: 10.1002/advs.202413253
• Publication Date: 2025-03-15T04:39:21Z
• Authors: Xin Yu; Yujing Song; Tao Dong; Wenlu Ouyang; Chao Quan; Liujiazi Shao; Leonard Barasa; Paul R. Thompson; Mao Zhang; Jianjie Ma; Katsuo Kurabayashi; Yongqing Li
• Keywords: Citrullination; Macrophage polarization

Abstract Mediating protein citrullination, peptidyl arginine deiminase 2 (PAD2) has recently been reported to influence macrophage phenotypes. However, the mechanisms of PAD2 on function in Pseudomonas aeruginosa (PA)‐induced acute lung injury syndrome (ALI) remains unclear. Utilizing single‐cell RNA sequencing and mass spectrometry‐based proteomics, a new citrullination site at 171 (R171) is discovered within nuclear factor‐ κB (NF‐κB) p65 catalyzed by PAD2, which modulates PAD2‐NF‐κB p65‐importin α3 pathway its downstream M1/M2 polarization. Building these findings, cell‐specific targeted therapeutic strategy using gold nanoparticles (AuNPs) conjugated with novel inhibitor, AFM41a, an intercellular adhesion molecule‐1 (ICAM‐1) antibody developed. This approach enables selective delivery inhibitor M1‐polarized macrophages PA‐infected alveolar niche. In vivo, this nanomedicine reduces excessive inflammation promotes M1‐to‐M2 polarization inhibit ALI. study highlights role PAD2‐mediated introduces promising nanoparticle‐based therapy for PA‐induced