The role of monocyte subpopulations in vascular injury following partial and transient depletion

Abstract

The innate immunity system plays a critical role in vascular repair and restenosis development. Liposomes encapsulating bisphosphonates (LipBPs), but not free BPs, suppress neointima formation following vascular injury mediated in part by monocytes. The objective of this study was to elucidate the role of monocyte subpopulations on vascular healing following LipBP treatment. The potency- and dose-dependent treatment effect of clodronate (CLOD) and alendronate (ALN) liposomes on restenosis inhibition, total monocyte depletion, and monocytes subpopulation was studied. Rats subjected to carotid injury were treated by a single IV injection of LipBPs at the time of injury. Low- and high-dose LipALN treatment (3 and 10 mg/kg, respectively) resulted in a dose-dependent effect on restenosis development after 30 days. Both doses of LipALN resulted in a dose-dependent inhibition of restenosis, but only high dose of LipALN depleted monocytes (−60.1 ± 4.4%, 48 h post injury). Although LipCLOD treatment (at an equivalent potency to 3 mg/kg alendronate) significantly reduced monocyte levels (72.1 ± 6%), no restenosis inhibition was observed. The major finding of this study is the correlation found between monocyte subclasses and restenosis inhibition. Non-classical monocyte (NCM) levels were found higher in LipALN-treated rats, but lower in LipCLOD-treated rats, 24 h after injury and treatment. We suggest that the inhibition of circulating monocyte subpopulations is the predominant mechanism by which LipBPs prevent restenosis. The effect of LipBP treatment on the monocyte subpopulation correlates with the dose and potency of LipBPs.

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References

  1. 1.

    Rogers C, Welt FG, Karnovsky MJ, Edelman ER. Monocyte recruitment and neointimal hyperplasia in rabbits. Coupled inhibitory effects of heparin. Arterioscler Thromb Vasc Biol. 1996;16(10):1312–8.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317(5838):666–70.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Hansson GK. Atherosclerosis-an immune disease: the Anitschkov lecture 2007. Atherosclerosis. 2009;202(1):2–10.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Fuster JJ, Fernandez P, Gonzalez-Navarro H, Silvestre C, Nabah YN, Andres V. Control of cell proliferation in atherosclerosis: insights from animal models and human studies. Cardiovasc Res. 2010;86(2):254–64.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Toutouzas K, Colombo A, Stefanadis C. Inflammation and restenosis after percutaneous coronary interventions. Eur Heart J. 2004;25(19):1679–87.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Schober A, Weber C. Mechanisms of monocyte recruitment in vascular repair after injury. Antioxid Redox Signal. 2005;7(9–10):1249–57.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Danenberg HD, Fishbein I, Gao J, Monkkonen J, Reich R, Gati I, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits. Circulation. 2002;106(5):599–605.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Danenberg HD, Fishbein I, Epstein H, Waltenberger J, Moerman E, Monkkonen J, et al. Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery. J Cardiovasc Pharmacol. 2003;42(5):671–9.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Danenberg HD, Golomb G, Groothuis A, Gao J, Epstein H, Swaminathan RV, et al. Liposomal alendronate inhibits systemic innate immunity and reduces in-stent neointimal hyperplasia in rabbits. Circulation. 2003;108(22):2798–804.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Epstein-Barash H, Gutman D, Markovsky E, Mishan-Eisenberg G, Koroukhov N, Szebeni J, et al. Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death. J Control Release. 2010;146(2):182–95.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Haber E, Afergan E, Epstein H, Gutman D, Koroukhov N, Ben-David M, et al. Route of administration-dependent anti-inflammatory effect of liposomal alendronate. J Control Release. 2010;148(2):226–33.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Cohen-Sela E, Rosenzweig O, Gao J, Epstein H, Gati I, Reich R, et al. Alendronate-loaded nanoparticles deplete monocytes and attenuate restenosis. J Control Release. 2006;113(1):23–30.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Gutman D, Golomb G. Liposomal alendronate for the treatment of restenosis. J Control Release. 2012;161(2):619–27.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Fazil M, Baboota S, Sahni JK, Ameeduzzafar AJ. Bisphosphonates: therapeutics potential and recent advances in drug delivery. Drug Deliv. 2015;22(1):1–9.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Banai S, Finkelstein A, Almagor Y, Assali A, Hasin Y, Rosenschein U, et al. Targeted anti-inflammatory systemic therapy for restenosis: the Biorest Liposomal Alendronate with Stenting sTudy (BLAST)—a double blind, randomized clinical trial. Am Heart J. 2013;165(2):234–40.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    ClinicalTrials.gov. Biorest liposomal alendronate administration for diabetic patients undergoing Drug-Eluting Stent Percutaneous Coronary Intervention 2016 [updated 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02645799?term=liposomes+alendronate&rank=2.

  17. 17.

    Ziegler-Heitbrock L. Monocyte subsets in man and other species. Cell Immunol. 2014;289(1–2):135–9.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Moniuszko M, Bodzenta-Lukaszyk A, Kowal K, Lenczewska D, Dabrowska M. Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients. Clin Immunol. 2009;130(3):338–46.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Zhou X, Liu XL, Ji WJ, Liu JX, Guo ZZ, Ren D, et al. The kinetics of circulating monocyte subsets and monocyte-platelet aggregates in the acute phase of ST-elevation myocardial infarction: associations with 2-year cardiovascular events. Medicine (Baltimore). 2016;95(18):e3466.

    Article  CAS  Google Scholar 

  21. 21.

    Liu Y, Imanishi T, Ikejima H, Tsujioka H, Ozaki Y, Kuroi A, et al. Association between circulating monocyte subsets and in-stent restenosis after coronary stent implantation in patients with ST-elevation myocardial infarction. Circ J. 2010;74(12):2585–91.

    Article  PubMed  Google Scholar 

  22. 22.

    Sunderkotter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol. 2004;172(7):4410–7.

    Article  PubMed  Google Scholar 

  23. 23.

    Yrlid U, Jenkins CD, MacPherson GG. Relationships between distinct blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under steady-state conditions. J Immunol. 2006;176(7):4155–62.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Fairbairn CE, Sayette MA. The effect of alcohol on emotional inertia: a test of alcohol myopia. J Abnorm Psychol. 2013;122(3):770–81.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Golomb G, Fishbein I, Banai S, Mishaly D, Moscovitz D, Gertz SD, et al. Controlled delivery of a tyrphostin inhibits intimal hyperplasia in a rat carotid artery injury model. Atherosclerosis. 1996;125(2):171–82.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Epstein H, Gutman D, Cohen-Sela E, Haber E, Elmalak O, Koroukhov N, et al. Preparation of alendronate liposomes for enhanced stability and bioactivity: in vitro and in vivo characterization. AAPS J. 2008;10(4):505–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Epstein H, Berger V, Levi I, Eisenberg G, Koroukhov N, Gao J, et al. Nanosuspensions of alendronate with gallium or gadolinium attenuate neointimal hyperplasia in rats. J Control Release. 2007;117(3):322–32.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Aizik G, Waiskopf N, Agbaria M, Levi-Kalisman Y, Banin U. Golomb G. ACS Nano: Delivery of Liposomal Quantum Dots via Monocytes for Imaging of Inflamed Tissue; 2017.

    Google Scholar 

  29. 29.

    Lang JK. Quantitative determination of cholesterol in liposome drug products and raw materials by high-performance liquid chromatography. J Chromatogr. 1990;507:157–63.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Holt AW, Tulis DA. Experimental rat and mouse carotid artery surgery: injury & remodeling studies. ISRN Minim Invasive Surg 2013;2013.

  31. 31.

    Fishbein I, Brauner R, Chorny M, Gao J, Chen X, Laks H, et al. Local delivery of mithramycin restores vascular reactivity and inhibits neointimal formation in injured arteries and vascular grafts. J Control Release. 2001;77(3):167–81.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Afergan E, Epstein H, Dahan R, Koroukhov N, Rohekar K, Danenberg HD, et al. Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes. J Control Release. 2008;132(2):84–90.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Chan JM, Rhee JW, Drum CL, Bronson RT, Golomb G, Langer R, et al. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles. Proc Natl Acad Sci U S A. 2011;108(48):19347–52.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Chan JM, Zhang L, Tong R, Ghosh D, Gao W, Liao G, et al. Spatiotemporal controlled delivery of nanoparticles to injured vasculature. Proc Natl Acad Sci U S A. 2010;107(5):2213–8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Dijkstra CD, Dopp EA, van den Berg TK, Damoiseaux JG. Monoclonal antibodies against rat macrophages. J Immunol Methods. 1994;174(1–2):21–3.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Strauss-Ayali D, Conrad SM, Mosser DM. Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol. 2007;82(2):244–52.

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Makkonen N, Salminen A, Rogers MJ, Frith JC, Urtti A, Azhayeva E, et al. Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci. 1999;8(2):109–18.

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Lehenkari PP, Kellinsalmi M, Napankangas JP, Ylitalo KV, Monkkonen J, Rogers MJ, et al. Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol. 2002;61(5):1255–62.

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Abbondanzo SJ, Chang SL. HIV-1 transgenic rats display alterations in immunophenotype and cellular responses associated with aging. PLoS One. 2014;9(8):e105256.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    Scriba A, Luciano L, Steiniger B. High-yield purification of rat monocytes by combined density gradient and immunomagnetic separation. J Immunol Methods. 1996;189(2):203–16.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Gilroy DW, Colville-Nash PR, McMaster S, Sawatzky DA, Willoughby DA, Lawrence T. Inducible cyclooxygenase-derived 15-deoxy(Delta)12-14PGJ2 brings about acute inflammatory resolution in rat pleurisy by inducing neutrophil and macrophage apoptosis. FASEB J. 2003;17(15):2269–71.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol. 2009;54(2):130–8.

    Article  PubMed  Google Scholar 

  44. 44.

    Barendregt CS, Van der Laan AM, Bongers IL, Van Nieuwenhuizen C. Adolescents in secure residential care: the role of active and passive coping on general well-being and self-esteem. Eur Child Adolesc Psychiatry. 2015;24(7):845–54.

    Article  PubMed  Google Scholar 

  45. 45.

    Ikejima H, Imanishi T, Tsujioka H, Kashiwagi M, Kuroi A, Tanimoto T, et al. Upregulation of fractalkine and its receptor, CX3CR1, is associated with coronary plaque rupture in patients with unstable angina pectoris. Circ J. 2010;74(2):337–45.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Crane MJ, Daley JM, van Houtte O, Brancato SK, Henry WL Jr, Albina JE. The monocyte to macrophage transition in the murine sterile wound. PLoS One. 2014;9(1):e86660.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. 47.

    Dal-Secco D, Wang J, Zeng Z, Kolaczkowska E, Wong CH, Petri B, et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J Exp Med. 2015;212(4):447–56.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011;29(11):1005–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. 49.

    Davis C, Fischer J, Ley K, Sarembock IJ. The role of inflammation in vascular injury and repair. J Thromb Haemost. 2003;1(8):1699–709.

    Article  PubMed  CAS  Google Scholar 

  50. 50.

    Inoue T, Node K. Molecular basis of restenosis and novel issues of drug-eluting stents. Circ J. 2009;73(4):615–21.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol. 2010;10(6):427–39.

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Gliem M, Mausberg AK, Lee JI, Simiantonakis I, van Rooijen N, Hartung HP, et al. Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann Neurol. 2012;71(6):743–52.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Chen L, Shao H, Zhou X, Liu G, Jiang J, Liu Z. Water-mediated cation intercalation of open-framework indium hexacyanoferrate with high voltage and fast kinetics. Nat Commun. 2016;7:11982.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Haber E, Danenberg HD, Koroukhov N, Ron-El R, Golomb G, Schachter M. Peritoneal macrophage depletion by liposomal bisphosphonate attenuates endometriosis in the rat model. Hum Reprod. 2009;24(2):398–407.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

GG is grateful to the Woll Sisters and Brothers Chair in Cardiovascular Diseases.

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Correspondence to Gershon Golomb.

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The protocol for this study was approved by the Institutional Committee for Animal Care and Use of the Hebrew University of Jerusalem.

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All institutional and national guidelines for the care and use of laboratories animals were followed.

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The authors declare that they have no conflict of interest.

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Grad, E., Zolotarevsky, K., Danenberg, H.D. et al. The role of monocyte subpopulations in vascular injury following partial and transient depletion. Drug Deliv. and Transl. Res. 8, 945–953 (2018). https://doi.org/10.1007/s13346-017-0404-5

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Keywords

  • Liposomes
  • Bisphosphonates
  • Monocytes subpopulation
  • Vascular injury