Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury
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 sin...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413253 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xin Yu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-31f04a8b77b548c0b6cb2dbeef8be2b3 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-31f04a8b77b548c0b6cb2dbeef8be2b32025-08-20T02:34:47ZengWileyAdvanced Science2198-38442025-05-011218n/an/a10.1002/advs.202413253Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung InjuryXin Yu0Yujing Song1Tao Dong2Wenlu Ouyang3Chao Quan4Liujiazi Shao5Leonard Barasa6Paul R. Thompson7Mao Zhang8Jianjie Ma9Katsuo Kurabayashi10Yongqing Li11Department of Surgery University of Michigan Health System Ann Arbor MI 48109 USADepartment of Mechanical and Aerospace Engineering New York University Tandon School of Engineering Brooklyn NY 11201 USADepartment of Surgery University of Michigan Health System Ann Arbor MI 48109 USADepartment of Surgery University of Michigan Health System Ann Arbor MI 48109 USADepartment of Surgery University of Michigan Health System Ann Arbor MI 48109 USADepartment of Surgery University of Michigan Health System Ann Arbor MI 48109 USAProgram in Chemical Biology, Department of Biochemistry and Molecular Biotechnology University of Massachusetts Chan Medical School Worcester MA 01605 USAProgram in Chemical Biology, Department of Biochemistry and Molecular Biotechnology University of Massachusetts Chan Medical School Worcester MA 01605 USADepartment of Emergency Medicine Second Affiliated Hospital Zhejiang University School of Medicine No.88 Jiefang Road Hangzhou Zhejiang 310009 ChinaDepartment of Surgery Division of Surgical Science University of Virginia Charlottesville VA 22903 USADepartment of Mechanical and Aerospace Engineering New York University Tandon School of Engineering Brooklyn NY 11201 USADepartment of Surgery University of Michigan Health System Ann Arbor MI 48109 USAAbstract 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.https://doi.org/10.1002/advs.202413253acute lung injurygold nanoparticlesICAM‐1macrophage polarizationNF‐κB p65PAD2 |
| spellingShingle | 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 Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury Advanced Science acute lung injury gold nanoparticles ICAM‐1 macrophage polarization NF‐κB p65 PAD2 |
| title | Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury |
| title_full | Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury |
| title_fullStr | Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury |
| title_full_unstemmed | Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury |
| title_short | Citrullination of NF‐κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury |
| title_sort | citrullination of nf κb p65 by pad2 as a novel therapeutic target for modulating macrophage polarization in acute lung injury |
| topic | acute lung injury gold nanoparticles ICAM‐1 macrophage polarization NF‐κB p65 PAD2 |
| url | https://doi.org/10.1002/advs.202413253 |
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