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Formyl peptide receptor 1 and its antagonist T0080 in atherosclerosis

Cell Death & Differentiation volume 32, pages 1859–1870 (2025)Cite this article

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Abstract

Focal inflammation and arterial damage driven by macrophages are key pathogenic processes in atherosclerosis. However, the mechanisms that regulate these processes remain poorly understood. In this study, we demonstrate that formyl peptide receptor 1 (FPR1) agonist, a mitochondrial N-formyl peptide, is elevated in the blood of patients with atherosclerosis and correlates with carotid stenosis. Macrophages expressing FPR1 were found in atherosclerotic lesions. Conditional deletion of Fpr1 in macrophages reduced plaque formation, local inflammation, and aortic atherosclerosis in apolipoprotein E (ApoE)−/− mice. FPR1 activates protein kinase C (PKC) in macrophages, promoting the production of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), which accelerates the apoptosis of endothelial cells and smooth muscle cells. To inhibit FPR1 bioactivity, we developed an antagonist, T0080. Therapeutic administration of T0080 attenuates atherosclerotic progression in ApoE−/− mice. Our findings highlight the pivotal role of FPR1 in macrophage-mediated atherosclerotic plaque formation and support further investigation of T0080-mediated FPR1 inhibition as a potential treatment for atherosclerosis.

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Fig. 1: Aberrant formyl peptide receptor 1 expression in atherosclerotic lesions and its clinical relevance in patients.
Fig. 2: OxLDL promotes the expression of FPR1 in macrophage.
Fig. 3: Macrophage FPR1 exacerbates arterial injury and subendothelial inflammation in ApoE −/−mice.
Fig. 4: Activation of macrophage FPR1 causes death of vascular smooth muscle cells and endothelial cells.
Fig. 5: FPR1 activates macrophage protein kinase C to produce TNF - α, IL-1 β and ROS causing cell injury of SMCs and ECs.
Fig. 6: Administration of FPR1 antagonist T0080 reduces atherosclerotic lesion, pro-inflammatory macrophage and endothelial cell death in ApoE−/− mice.
Fig. 7: Schematic diagram of FPR1 and its antagonist T0080 in atherosclerosis.

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Data availability

RNA-Seq data were obtained from NCBI’s Gene Expression Omnibus (GEO) database (GEO GSE155512, https://www.ncbi.nlm.nih.gov). Codes were implemented in R (version R-4.4.1) and are deposited in GitHub - snowinghere/R-code-for-FPR1-in-atherosclerosis. All other data are available from the corresponding author upon reasonable request.

References

  1. Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, et al. AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease: a report of the american heart association/american college of cardiology joint committee on clinical practice guidelines. Circulation 2023. 2023;148:e9–119.

    Google Scholar 

  2. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76:2982–3021.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hou P, Fang J, Liu Z, Shi Y, Agostini M, Bernassola F, et al. Macrophage polarization and metabolism in atherosclerosis. Cell Death Dis. 2023;14:691.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bjorkegren JLM, Lusis AJ. Atherosclerosis: recent developments. Cell. 2022;185:1630–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hwang SJ, Ahn BJ, Shin MW, Song YS, Choi Y, Oh GT, et al. miR-125a-5p attenuates macrophage-mediated vascular dysfunction by targeting Ninjurin1. Cell Death Differ. 2022;29:1199–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lusis AJ. Atherosclerosis. Nature. 2000;407:233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Swirski FK, Robbins CS, Nahrendorf M. Development and function of arterial and cardiac macrophages. Trends Immunol. 2016;37:32–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Clyburn C, Birren SJ. Crosstalk between nerves, immune cells and plaques drives atherosclerosis. Nature. 2022;605:32–4.

    Article  CAS  PubMed  Google Scholar 

  9. Yu EP, Bennett MR. The role of mitochondrial DNA damage in the development of atherosclerosis. Free Radic Biol Med. 2016;100:223–30.

    Article  CAS  PubMed  Google Scholar 

  10. Satish M, Agrawal DK. Atherothrombosis and the NLRP3 inflammasome - endogenous mechanisms of inhibition. Transl Res. 2020;215:75–85.

    Article  CAS  PubMed  Google Scholar 

  11. Khwaja B, Thankam FG, Agrawal DK. Mitochondrial DAMPs and altered mitochondrial dynamics in OxLDL burden in atherosclerosis. Mol Cell Biochem. 2021;476:1915–28.

    Article  CAS  PubMed  Google Scholar 

  12. Dorward DA, Lucas CD, Doherty MK, Chapman GB, Scholefield EJ, Conway Morris A, et al. Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome. Thorax. 2017;72:928–36.

    Article  PubMed  Google Scholar 

  13. Li Z, Li Y, Han J, Zhu Z, Li M, Liu Q, et al. Formyl peptide receptor 1 signaling potentiates inflammatory brain injury. Sci Transl Med. 2021;13:eabe9890.

  14. Liu M, Zhao J, Chen K, Bian X, Wang C, Shi Y, et al. G protein-coupled receptor FPR1 as a pharmacologic target in inflammation and human glioblastoma. Int Immunopharmacol. 2012;14:283–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tsai YF, Yang SC, Hwang TL. Formyl peptide receptor modulators: a patent review and potential applications for inflammatory diseases (2012-2015). Expert Opin Ther Pat. 2016;26:1139–56.

    Article  CAS  PubMed  Google Scholar 

  16. Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG. The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. Am J Pathol. 2015;185:1172–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee HY, Lee M, Bae YS. Formyl peptide receptors in cellular differentiation and inflammatory diseases. J Cell Biochem. 2017;118:1300–7.

    Article  CAS  PubMed  Google Scholar 

  18. Chen G, Wang X, Liao Q, Ge Y, Jiao H, Chen Q, et al. Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns. Nat Commun. 2022;13:5232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Petri MH, Laguna-Fernandez A, Gonzalez-Diez M, Paulsson-Berne G, Hansson GK, Back M. The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability. Cardiovasc Res. 2015;105:65–74.

    Article  CAS  PubMed  Google Scholar 

  20. Drechsler M, de Jong R, Rossaint J, Viola JR, Leoni G, Wang JM, et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ Res. 2015;116:827–35.

    Article  CAS  PubMed  Google Scholar 

  21. Gemperle C, Schmid M, Herova M, Marti-Jaun J, Wuest SJ, Loretz C, et al. Regulation of the formyl peptide receptor 1 (FPR1) gene in primary human macrophages. PloS One. 2012;7:e50195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rhoads JP, Major AS. How Oxidized Low-density lipoprotein activates inflammatory responses. Crit Rev Immunol. 2018;38:333–42.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang Y, Fatima M, Hou S, Bai L, Zhao S, Liu E. Research methods for animal models of atherosclerosis (Review). Mol Med Rep. 2021;24:871.

  24. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994;14:133–40.

    Article  CAS  PubMed  Google Scholar 

  25. Wenceslau CF, McCarthy CG, Szasz T, Goulopoulou S, Webb RC. Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome. Am J Physiol Heart Circ Physiol. 2015;308:H768–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li J, Chordia MD, Zhang Y, Zong H, Pan D, Zuo Z. Critical role of FPR1 in splenocyte migration into brain to worsen inflammation and ischemic brain injury in mice. Theranostics. 2022;12:3024–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330:362–6.

    Article  CAS  PubMed  Google Scholar 

  28. Leslie J, Millar BJ, Del Carpio Pons A, Burgoyne RA, Frost JD, Barksby BS, et al. FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis. JCI Insight. 2020;5:e125937.

  29. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fan X, Han J, Zhong L, Zheng W, Shao R, Zhang Y, et al. Macrophage-derived GSDMD plays an essential role in atherosclerosis and cross talk between macrophages via the mitochondria-STING-IRF3/NF-kappaB axis. Arterioscler Thromb Vasc Biol. 2024;44:1365–78.

    Article  CAS  PubMed  Google Scholar 

  31. Olsen MB, Gregersen I, Sandanger O, Yang K, Sokolova M, Halvorsen BE, et al. Targeting the inflammasome in cardiovascular disease. JACC Basic Transl Sci. 2022;7:84–98.

    Article  PubMed  Google Scholar 

  32. Opoku E, Traughber CA, Zhang D, Iacano AJ, Khan M, Han J, et al. Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis. Front Cell Dev Biol. 2021;9:715211.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wei Y, Lan B, Zheng T, Yang L, Zhang X, Cheng L, et al. GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis. Nat Commun. 2023;14:929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tall AR, Bornfeldt KE. Inflammasomes and atherosclerosis: a mixed picture. Circ Res. 2023;132:1505–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol. 2017;70:2278–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.

    Article  CAS  PubMed  Google Scholar 

  37. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.

    Article  PubMed  PubMed Central  Google Scholar 

  39. He HQ, Ye RD. The formyl peptide receptors: diversity of ligands and mechanism for recognition. Molecules. 2017;22:455.

  40. Mormile I, Rossi FW, Prevete N, Granata F, Pucino V, de Paulis A. The N-formyl peptide receptors and rheumatoid arthritis: a dangerous liaison or confusing relationship? Front Immunol. 2021;12:685214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. van Leeuwen M, Damoiseaux J, Duijvestijn A, Tervaert JW. The therapeutic potential of targeting B cells and anti-oxLDL antibodies in atherosclerosis. Autoimmun Rev. 2009;9:53–7.

    Article  PubMed  Google Scholar 

  42. Hartley A, Haskard D, Khamis R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis - novel insights and future directions in diagnosis and therapy. Trends Cardiovasc Med. 2019;29:22–6.

    Article  CAS  PubMed  Google Scholar 

  43. Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Cayatte AJ, Rozek MM. Pathogenesis of the atherosclerotic lesion. Implications for diabetes mellitus. Diabetes Care. 1992;15:1156–67.

    Article  CAS  PubMed  Google Scholar 

  44. Xu Y, Kong X, Zhou H, Zhang X, Liu J, Yan J, et al. oxLDL/beta2GPI/anti-beta2GPI complex induced macrophage differentiation to foam cell involving TLR4/NF-kappa B signal transduction pathway. Thromb Res. 2014;134:384–92.

    Article  CAS  PubMed  Google Scholar 

  45. Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, et al. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 george lyman duff memorial lecture. Arterioscler Thromb Vasc Biol. 1996;16:831–42.

    Article  CAS  PubMed  Google Scholar 

  46. Navab M, Hama-Levy S, Van Lenten BJ, Fonarow GC, Cardinez CJ, Castellani LW, et al. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest. 1997;99:2005–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Back M, Yurdagul A Jr, Tabas I, Oorni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16:389–406.

    PubMed  PubMed Central  Google Scholar 

  48. Deroissart J, Porsch F, Koller T, Binder CJ. Anti-inflammatory and immunomodulatory therapies in atherosclerosis. Handb Exp Pharm. 2022;270:359–404.

    Article  CAS  Google Scholar 

  49. Hetherington I, Totary-Jain H. Anti-atherosclerotic therapies: milestones, challenges, and emerging innovations. Mol Ther. 2022;30:3106–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Grant EG, Benson CB, Moneta GL, Alexandrov AV, Baker JD, Bluth EI, et al. Carotid artery stenosis: gray-scale and doppler US diagnosis-society of radiologists in ultrasound consensus conference. Radiology. 2003;229:340–6.

    Article  PubMed  Google Scholar 

  51. Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KR, Xiao L, et al. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest. 2016;126:1607.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Pan H, Xue C, Auerbach BJ, Fan J, Bashore AC, Cui J, et al. Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human. Circulation. 2020;142:2060–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Diotallevi M, Nicol T, Ayaz F, Bailey J, Shaw A, McNeill E, et al. Isolation and in vitro culture of bone marrow-derived macrophages for the study of NO-redox biology. J Vis Exp. 2022;183:e62834.

  54. Chen Y, Wu X, Zhang J, Pan G, Wang X, Guo X, et al. Amino acid starvation-induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance. EMBO Rep. 2022;23:e53373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Plaisance-Bonstaff K, Faia C, Wyczechowska D, Jeansonne D, Vittori C, Peruzzi F. Isolation, transfection, and culture of primary human monocytes. J Vis Exp. 2019;154:e59967.

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Acknowledgements

We thank Drs. L. Zheng, M. Liu and Y. Zhu for fruitful discussions, and Dr. S.X. Shi for editorial assistance.

Funding

This work was supported by the National Natural Science Foundation of China (82471312, 82320108007 and 81830038) and Tianjin Science and Technology Commission Foundation (21JCYBJC00770).

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Authors and Affiliations

  1. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Yu-Jing Li, Xue Zhao, Siting Wu, Nan Yao, Xueyu Zhang, Yanyan Liu, Xiaobing Tian, Yulin Li, Fu-Dong Shi & Zhiguo Li

  2. Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Yu-Jing Li, Bin Gao & Fu-Dong Shi

  3. Department of Neurology, University of California, San Francisco, CA, 94143, USA

    S. Claiborne Johnston

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Contributions

ZL, F-DS and SCJ formulated the conception and design of this study. YL, XZ, SW, YL, XT, XZ, YL and NY performed the experiments, YL, XZ, BG, F-DS, ZL and SW analyzed and interpreted the results. ZL, F-DS, YL, XZ and SCJ wrote and edited the manuscript.

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Correspondence to Fu-Dong Shi or Zhiguo Li.

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The authors declare no competing interests.

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All experiments involving human tissue samples were approved by the Medical Ethics Committee of Tianjin Medical University General Hospital (Tianjin, China). All animal experiments were approved by the Laboratory Animal Management and Ethics Committee of Tianjin Medical University General Hospital (Tianjin, China) and were performed in accordance with the “China’s Guidelines on Welfare and Ethical Review for Laboratory Animals”.

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Li, YJ., Zhao, X., Wu, S. et al. Formyl peptide receptor 1 and its antagonist T0080 in atherosclerosis. Cell Death Differ 32, 1859–1870 (2025). https://doi.org/10.1038/s41418-025-01506-7

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