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Updated: May 22, 2025
Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Published on: June 23, 2013
Citrullination of NF-κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute
Xin Yu1,2, Yujing Song3,4, Tao Dong1,5
1Department of Surgery, University of Michigan Health System, Ann Arbor, MI, 48109, USA.
Abstract:
Mediating protein citrullination, peptidyl arginine deiminase 2 (PAD2) has recently been reported to influence macrophage phenotypes. However, the mechanisms of PAD2 on macrophage 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 arginine 171 (R171) is discovered within nuclear factor- κB (NF-κB) p65 catalyzed by PAD2, which modulates PAD2-NF-κB p65-importin α3 pathway and its downstream M1/M2 macrophage polarization. Building on these findings, a cell-specific targeted therapeutic strategy using gold nanoparticles (AuNPs) conjugated with a novel PAD2 inhibitor, AFM41a, and an intercellular adhesion molecule-1 (ICAM-1) antibody is developed. This approach enables the selective delivery of the inhibitor to M1-polarized macrophages in the PA-infected alveolar niche. In vivo, this nanomedicine reduces excessive inflammation and promotes M1-to-M2 polarization to inhibit ALI. This study highlights the role of PAD2-mediated citrullination in macrophage polarization and introduces a promising nanoparticle-based therapy for PA-induced ALI.
Insights
Peptidyl arginine deiminase 2 (PAD2) drives inflammation in acute lung injury (ALI) by altering macrophage polarization. A novel nanoparticle therapy targets PAD2 in M1 macrophages, reducing inflammation and promoting healing in Pseudomonas aeruginosa-induced ALI.
Area of Science:
- Immunology
- Molecular Biology
- Nanomedicine
Background:
- Peptidyl arginine deiminase 2 (PAD2) influences macrophage phenotypes.
- The role of PAD2 in Pseudomonas aeruginosa (PA)-induced acute lung injury (ALI) remains unclear.
- Understanding PAD2's mechanism in macrophage polarization is crucial for ALI treatment.
Purpose of the Study:
- To elucidate the mechanisms of PAD2 in PA-induced ALI.
- To identify novel PAD2 targets and pathways involved in macrophage polarization.
- To develop a targeted nanomedicine for ALI treatment.
Main Methods:
- Single-cell RNA sequencing and mass spectrometry-based proteomics were employed.
- A novel citrullination site (R171) in NF-κB p65 was identified.
- A targeted nanoparticle delivery system using gold nanoparticles (AuNPs), a PAD2 inhibitor (AFM41a), and an ICAM-1 antibody was developed.
Main Results:
- PAD2-mediated citrullination at R171 modulates the PAD2-NF-κB p65-importin α3 pathway.
- This pathway regulates M1/M2 macrophage polarization in ALI.
- The targeted nanomedicine selectively delivered the PAD2 inhibitor to M1 macrophages, reducing inflammation and promoting M1-to-M2 polarization in vivo.
- The nanomedicine effectively inhibited ALI.
Conclusions:
- PAD2-mediated citrullination plays a significant role in macrophage polarization during ALI.
- Targeting PAD2 with a novel nanoparticle-based strategy shows promise for treating PA-induced ALI.
- This study introduces a new therapeutic avenue for inflammatory lung diseases.
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