Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis
Abstract Rheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as a therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthri...
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Springer Nature
2025-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00227-1 |
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| author | Andreas Margraf Jianmin Chen Marilena Christoforou Pol Claria-Ribas Ayda Henriques Schneider Chiara Cecconello Weifeng Bu Paul R C Imbert Thomas D Wright Stefan Russo Isobel A Blacksell Duco S Koenis Jesmond Dalli John A Lupisella Nicholas R Wurtz Ricardo A Garcia Dianne Cooper Lucy V Norling Mauro Perretti |
| author_facet | Andreas Margraf Jianmin Chen Marilena Christoforou Pol Claria-Ribas Ayda Henriques Schneider Chiara Cecconello Weifeng Bu Paul R C Imbert Thomas D Wright Stefan Russo Isobel A Blacksell Duco S Koenis Jesmond Dalli John A Lupisella Nicholas R Wurtz Ricardo A Garcia Dianne Cooper Lucy V Norling Mauro Perretti |
| author_sort | Andreas Margraf |
| collection | DOAJ |
| description | Abstract Rheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as a therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthritic mice on high levels of dietary homocysteine develop cardiac diastolic dysfunction and reduced lung compliance, mirroring two comorbidities in RA. Therapeutic administration of a small molecule FPR2 agonist (BMS986235) to hyper-homocysteine arthritic mice prevented diastolic dysfunction (monitored by echocardiography) and restored lung compliance. These tissue-specific effects were secondary to reduced neutrophil infiltration, modulation of fibroblast activation and phenotype (in the heart) and attenuation of monocyte and macrophage numbers (in the lung). A dual FPR1/2 agonist (compound 43) failed to prevent the reduction in lung compliance of arthritic mice and promoted the accumulation of inflammatory monocytes and pro-fibrotic macrophages in lung parenchyma. This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports the therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides. |
| format | Article |
| id | doaj-art-8922f9ca68ee48b7bff042e9da2a6c53 |
| institution | OA Journals |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-8922f9ca68ee48b7bff042e9da2a6c532025-08-20T01:51:30ZengSpringer NatureEMBO Molecular Medicine1757-46842025-04-011751153118310.1038/s44321-025-00227-1Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritisAndreas Margraf0Jianmin Chen1Marilena Christoforou2Pol Claria-Ribas3Ayda Henriques Schneider4Chiara Cecconello5Weifeng Bu6Paul R C Imbert7Thomas D Wright8Stefan Russo9Isobel A Blacksell10Duco S Koenis11Jesmond Dalli12John A Lupisella13Nicholas R Wurtz14Ricardo A Garcia15Dianne Cooper16Lucy V Norling17Mauro Perretti18William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonDepartment of Cardiovascular and Fibrosis Drug Discovery, Bristol Myers SquibbDepartment of Cardiovascular and Fibrosis Drug Discovery, Bristol Myers SquibbDepartment of Cardiovascular and Fibrosis Drug Discovery, Bristol Myers SquibbWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonWilliam Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of LondonAbstract Rheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as a therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthritic mice on high levels of dietary homocysteine develop cardiac diastolic dysfunction and reduced lung compliance, mirroring two comorbidities in RA. Therapeutic administration of a small molecule FPR2 agonist (BMS986235) to hyper-homocysteine arthritic mice prevented diastolic dysfunction (monitored by echocardiography) and restored lung compliance. These tissue-specific effects were secondary to reduced neutrophil infiltration, modulation of fibroblast activation and phenotype (in the heart) and attenuation of monocyte and macrophage numbers (in the lung). A dual FPR1/2 agonist (compound 43) failed to prevent the reduction in lung compliance of arthritic mice and promoted the accumulation of inflammatory monocytes and pro-fibrotic macrophages in lung parenchyma. This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports the therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides.https://doi.org/10.1038/s44321-025-00227-1Resolution PharmacologyPro-resolving GPCRHFpEFLung InjuryRheumatoid Arthritis |
| spellingShingle | Andreas Margraf Jianmin Chen Marilena Christoforou Pol Claria-Ribas Ayda Henriques Schneider Chiara Cecconello Weifeng Bu Paul R C Imbert Thomas D Wright Stefan Russo Isobel A Blacksell Duco S Koenis Jesmond Dalli John A Lupisella Nicholas R Wurtz Ricardo A Garcia Dianne Cooper Lucy V Norling Mauro Perretti Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis EMBO Molecular Medicine Resolution Pharmacology Pro-resolving GPCR HFpEF Lung Injury Rheumatoid Arthritis |
| title | Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis |
| title_full | Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis |
| title_fullStr | Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis |
| title_full_unstemmed | Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis |
| title_short | Formyl-peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis |
| title_sort | formyl peptide receptor type 2 activation mitigates heart and lung damage in inflammatory arthritis |
| topic | Resolution Pharmacology Pro-resolving GPCR HFpEF Lung Injury Rheumatoid Arthritis |
| url | https://doi.org/10.1038/s44321-025-00227-1 |
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