LDL-binding IL-10 reduces vascular inflammation in atherosclerotic mice

1. Valanti, E.-K. et al. Advances in biological therapies for dyslipidemias and atherosclerosis. Metabolism 116, 154461 (2021).

   Article  CAS  PubMed  Google Scholar 

2. Hetherington, I. & Totary-Jain, H. Anti-atherosclerotic therapies: milestones, challenges, and emerging innovations. Mol. Ther. 30, 3106–3117 (2022).

   Article  CAS  PubMed  PubMed Central  Google Scholar 

3. Meza-Contreras, A. et al. Statin intolerance management: a systematic review. Endocrine 79, 430–436 (2023).

   Article  CAS  PubMed  Google Scholar 

4. Banach, M., Stulc, T., Dent, R. & Toth, P. P. Statin non-adherence and residual cardiovascular risk: there is need for substantial improvement. Int. J. Cardiol. 225, 184–196 (2016).

   Article  PubMed  Google Scholar 

5. Ahmad, F. B. & Anderson, R. N. The leading causes of death in the US for 2020. JAMA 325, 1829–1830 (2021).

   Article  CAS  PubMed  PubMed Central  Google Scholar 

6. Gaidai, O., Cao, Y. & Loginov, S. Global cardiovascular diseases death rate prediction. Curr. Probl. Cardiol. 48, 101622 (2023).

7. Gisterå, A. & Hansson, G. K. The immunology of atherosclerosis. Nat. Rev. Nephrol. 13, 368–380 (2017).

   Article  PubMed  Google Scholar 

8. Wolf, D. & Ley, K. Immunity and inflammation in atherosclerosis. Circ. Res. 124, 315–327 (2019).

   Article  CAS  PubMed  PubMed Central  Google Scholar 

9. Libby, P. Inflammation in atherosclerosis—no longer a theory. Clin. Chem. 67, 131–142 (2021).

   Article  PubMed  Google Scholar 

10. Orekhov, A. N. LDL and foam cell formation as the basis of atherogenesis. Curr. Opin. Lipidol. 29, 279–284 (2018).

    Article  CAS  PubMed  Google Scholar 

11. Yuan, Y., Li, P. & Ye, J. Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis. Protein Cell 3, 173–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

12. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

13. Engelen, S. E., Robinson, A. J., Zurke, Y.-X. & Monaco, C. Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat. Rev. Cardiol. 19, 522–542 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

14. Moreno-Gonzalez, M. A., Ortega-Rivera, O. A. & Steinmetz, N. F. Two decades of vaccine development against atherosclerosis. Nano Today 50, 101822 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

15. Pinderski Oslund, L. J. et al. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arter. Thromb. Vasc. Biol. 19, 2847–2853 (1999).

    Article  CAS  Google Scholar 

16. Mallat, Z. et al. Protective role of interleukin-10 in atherosclerosis. Circ. Res. 85, e17–e24 (1999).

    Article  CAS  PubMed  Google Scholar 

17. Caligiuri, G. et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol. Med. 9, 10–17 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

18. Namiki, M. et al. Intramuscular gene transfer of interleukin-10 cDNA reduces atherosclerosis in apolipoprotein E-knockout mice. Atherosclerosis 172, 21–29 (2004).

    Article  CAS  PubMed  Google Scholar 

19. Yoshioka, T. et al. Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice. Gene Ther. 11, 1772–1779 (2004).

    Article  CAS  PubMed  Google Scholar 

20. Kamaly, N. et al. Targeted interleukin-10 nanotherapeutics developed with a microfluidic chip enhance resolution of inflammation in advanced atherosclerosis. ACS Nano 10, 5280–5292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

21. Kim, M. et al. Targeted delivery of anti-inflammatory cytokine by nanocarrier reduces atherosclerosis in Apo E−/-mice. Biomaterials 226, 119550 (2020).

    Article  CAS  PubMed  Google Scholar 

22. Silver, A. B., Leonard, E. K., Gould, J. R. & Spangler, J. B. Engineered antibody fusion proteins for targeted disease therapy. Trends Pharmacol. Sci. 42, 1064–1081 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

23. Kita, T. et al. Role of oxidized LDL in atherosclerosis. Ann. N. Y. Acad. Sci. 947, 199–206 (2001).

    Article  CAS  PubMed  Google Scholar 

24. Schiopu, A. et al. Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis. Circulation 110, 2047–2052 (2004).

    Article  CAS  PubMed  Google Scholar 

25. Schiopu, A. et al. Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in Apobec-1^−/−/low-density lipoprotein receptor^−/− mice. J. Am. Coll. Cardiol. 50, 2313–2318 (2007).

    Article  CAS  PubMed  Google Scholar 

26. Nilsson, J. & Carlsson, R. Oxidized LDL and Antibodies Thereto for the Treatment of Atherosclerotic Plaques. Publication No. WO 2008/104194 A1 (World Intellectual Property Organization, 2007).

27. Makabe, K., Tereshko, V., Gawlak, G., Yan, S. & Koide, S. Atomic-resolution crystal structure of Borrelia burgdorferi outer surface protein A via surface engineering. Protein Sci. 15, 1907–1914 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

28. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

29. Gautier, E. L., Jakubzick, C. & Randolph, G. J. Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arter. Thromb. Vasc. Biol. 29, 1412–1418 (2009).

    Article  CAS  Google Scholar 

30. Georgakis, M. K., Bernhagen, J., Heitman, L. H., Weber, C. & Dichgans, M. Targeting the CCL2–CCR2 axis for atheroprotection. Eur. Heart J. 43, 1799–1808 (2022).

    Article  CAS  PubMed  Google Scholar 

31. Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

32. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  CAS  PubMed  Google Scholar 

33. Choudhury, R. P., Lee, J. M. & Greaves, D. R. Mechanisms of disease: macrophage-derived foam cells emerging as therapeutic targets in atherosclerosis. Nat. Clin. Pract. Cardiovasc. Med. 2, 309–315 (2005).

    Article  CAS  PubMed  Google Scholar 

34. Maguire, E. M., Pearce, S. W. & Xiao, Q. Foam cell formation: a new target for fighting atherosclerosis and cardiovascular disease. Vasc. Pharmacol. 112, 54–71 (2019).

    Article  CAS  Google Scholar 

35. Reardon, C. A. & Getz, G. S. Mouse models of atherosclerosis. Curr. Opin. Lipidol. 12, 167–173 (2001).

    Article  CAS  PubMed  Google Scholar 

36. Matsuura, E., Hughes, G. R. & Khamashta, M. A. Oxidation of LDL and its clinical implication. Autoimmun. Rev. 7, 558–566 (2008).

    Article  CAS  PubMed  Google Scholar 

37. Li, S. et al. Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. Mol. Metab. 2, 256–269 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

38. Peters, E. B. & Kibbe, M. R. Nanomaterials to resolve atherosclerosis. ACS Biomater. Sci. Eng. 6, 3693–3712 (2020).

    Article  CAS  PubMed  Google Scholar 

39. Nong, J., Glassman, P. M. & Muzykantov, V. R. Targeting vascular inflammation through emerging methods and drug carriers. Adv. Drug Deliv. Rev. 184, 114180 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

40. Shuvaev, V. V. et al. PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. FASEB J. 25, 348 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

41. Shuvaev, V. V. et al. Modulation of endothelial targeting by size of antibody–antioxidant enzyme conjugates. J. Control. Release 149, 236–241 (2011).

    Article  CAS  PubMed  Google Scholar 

42. Hutmacher, C. & Neri, D. Antibody–cytokine fusion proteins: biopharmaceuticals with immunomodulatory properties for cancer therapy. Adv. Drug Deliv. Rev. 141, 67–91 (2019).

    Article  CAS  PubMed  Google Scholar 

43. Bootz, F. & Neri, D. Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions. Drug Discov. Today 21, 180–189 (2016).

    Article  CAS  PubMed  Google Scholar 

44. Schwager, K. et al. Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immunocytokine which inhibits the progression of collagen-induced arthritis. Arthritis Res. Ther. 11, R142 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

45. Galeazzi, M. et al. FRI0118 Dekavil (F8IL10)–Update on the Results of Clinical Trials Investigating the Immunocytokine in Patients with Rheumatoid Arthritis (BMJ Publishing Group, 2018).

46. Toshima, S. et al. Circulating oxidized low density lipoprotein levels: a biochemical risk marker for coronary heart disease. Arter. Thromb. Vasc. Biol. 20, 2243–2247 (2000).

    Article  CAS  Google Scholar 

47. Boullier, A. et al. Scavenger receptors, oxidized LDL, and atherosclerosis. Ann. N. Y. Acad. Sci. 947, 214–223 (2001).

    Article  CAS  PubMed  Google Scholar 

48. Sziksz, E. et al. Fibrosis related inflammatory mediators: role of the IL-10 cytokine family. Mediators Inflamm. 2015, 764641 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

49. Getz, G. S. & Reardon, C. A. Do the Apoe^−/− and Ldlr^−/− mice yield the same insight on atherogenesis? Arter. Thromb. Vasc. Biol. 36, 1734–1741 (2016).

    Article  CAS  Google Scholar 

50. Sakkers, T. R. et al. Sex differences in the genetic and molecular mechanisms of coronary artery disease. Atherosclerosis 384, 117279 (2023).

51. Gonçalves, I. et al. Identification of the target for therapeutic recombinant anti-apoB-100 peptide antibodies in human atherosclerotic lesions. Atherosclerosis 205, 96–100 (2009).

    Article  PubMed  Google Scholar 

52. Watkins, E. A. et al. Persistent antigen exposure via the eryptotic pathway drives terminal T cell dysfunction. Sci. Immunol. 6, eabe1801 (2021).

    Article  CAS  PubMed  Google Scholar 

53. Butcher, M. J., Herre, M., Ley, K. & Galkina, E. Flow cytometry analysis of immune cells within murine aortas. J. Vis. Exp. https://doi.org/10.3791/2848 (2011).

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Authors and Affiliations

1. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA

   Lisa R. Volpatti, Salvador Norton de Matos, Gustavo Borjas, Taryn N. Beckman, Joseph W. Reda, Elyse A. Watkins, Zhengjie Zhou & Jeffrey A. Hubbell

2. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA

   Lisa R. Volpatti

3. Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA

   Lisa R. Volpatti

4. Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA

   Salvador Norton de Matos

5. Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, IL, USA

   Taryn N. Beckman & Yun Fang

6. Department of Medicine, University of Chicago, Chicago, IL, USA

   Zhengjie Zhou & Yun Fang

7. Animal Resources Center, University of Chicago, Chicago, IL, USA

   Mindy Nguyen & Ani Solanki

8. Committee on Immunology, University of Chicago, Chicago, IL, USA

   Jeffrey A. Hubbell

9. Committee on Cancer Biology, University of Chicago, Chicago, IL, USA

   Jeffrey A. Hubbell

10. Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, New York, NY, USA

    Jeffrey A. Hubbell

11. Departments of Biology and Chemistry, Faculty of Arts and Science, New York University, New York, NY, USA

    Jeffrey A. Hubbell

12. Department of Biochemistry and Molecular Pharmacology, Grossman School of Medicine, NYU Langone Health, New York, NY, USA

    Jeffrey A. Hubbell

Contributions

L.R.V. conceptualized the project, designed the methodology, performed validation, formal analysis, investigation, data curation and visualization, supervised and administered the project, acquired funding and wrote the original manuscript draft. S.N.d.M. designed the methodology and software, performed validation, formal analysis, investigation and visualization, and reviewed and edited the manuscript. G.B. designed the methodology and software, conducted formal analysis and investigation, and reviewed and edited the manuscript. T.N.B. designed the methodology, conducted formal analysis and investigation, and reviewed and edited the manuscript. J.W.R. designed the methodology, conducted investigation, and reviewed and edited the manuscript. E.A.W. designed the methodology, conducted investigation, procured resources, and reviewed and edited the manuscript. Z.Z. designed the methodology, conducted investigation, and reviewed and edited the manuscript. M.N. designed the methodology, conducted investigation, and reviewed and edited the manuscript. A.S. designed the methodology, conducted investigation, and reviewed and edited the manuscript. Y.F. designed the methodology, procured resources, supervised the project, and reviewed and edited the manuscript. J.A.H. conceptualized the project, procured resources, supervised and administered the project, acquired funding, and reviewed and edited the manuscript.

Corresponding authors

Correspondence to Lisa R. Volpatti or Jeffrey A. Hubbell.

Competing interests

The authors declare no competing interests.

Peer review information

Nature Biomedical Engineering thanks Prediman Shah and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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