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Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils

Abstract

Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell—polymorphonuclear neutrophils—to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration1,2. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation3. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks ‘outside-in’ β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

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Figure 1: Uptake of albumin nanoparticles by adherent neutrophils in venules.
Figure 2: Characteristics of internalization properties of different types of albumin nanoparticle.
Figure 3: Contribution of FcγRIII mechanism in mediating albumin nanoparticle internalization.
Figure 4: Therapeutic activity of albumin nanoparticles in vascular inflammation and lung injury models.

References

  1. Hu, G., Malik, A. B. & Minshall, R. D. Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Crit. Care Med. 38, 194–201 (2010).

    CAS  Article  Google Scholar 

  2. Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

    CAS  Article  Google Scholar 

  3. Wang, Z., Tiruppathi, C., Cho, J., Minshall, R. D. & Malik, A. B. Delivery of nanoparticle: complexed drugs across the vascular endothelial barrier via caveolae. IUBMB Life 63, 659–667 (2011).

    CAS  Article  Google Scholar 

  4. Xu, J. et al. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins. Nature Immunol. 9, 880–886 (2008).

    CAS  Article  Google Scholar 

  5. Wong, C. H., Heit, B. & Kubes, P. Molecular regulators of leucocyte chemotaxis during inflammation. Cardiovasc. Res. 86, 183–191 (2010).

    CAS  Article  Google Scholar 

  6. Phillipson, M. & Kubes, P. The neutrophil in vascular inflammation. Nature Med. 17, 1381–1390 (2011).

    CAS  Article  Google Scholar 

  7. Wagner, D. D. & Frenette, P. S. The vessel wall and its interactions. Blood 111, 5271–5281 (2008).

    CAS  Article  Google Scholar 

  8. Lockwood, C. M. et al. Anti-adhesion molecule therapy as an interventional strategy for autoimmune inflammation. Clin. Immunol. 93, 93–106 (1999).

    CAS  Article  Google Scholar 

  9. Sharar, S. R., Winn, R. K., Murry, C. E., Harlan, J. M. & Rice, C. L. A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits. Surgery 110, 213–219 (1991).

    CAS  Google Scholar 

  10. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nature Rev. Drug Discov. 9, 615–627 (2010).

    CAS  Article  Google Scholar 

  11. Farokhzad, O. C. & Langer, R. Impact of nanotechnology on drug delivery. ACS Nano 3, 16–20 (2009).

    CAS  Article  Google Scholar 

  12. Schroeder, A. et al. Treating metastatic cancer with nanotechnology. Nature Rev. Cancer 12, 39–50 (2012).

    CAS  Article  Google Scholar 

  13. Hahm, E. et al. Extracellular protein disulfide isomerase regulates ligand-binding activity of αMβ2 integrin and neutrophil recruitment during vascular inflammation. Blood 121, 3789–3800 (2013).

    CAS  Article  Google Scholar 

  14. Hidalgo, A. et al. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nature Med. 15, 384–391 (2009).

    CAS  Article  Google Scholar 

  15. Evans, R., Lellouch, A. C., Svensson, L., McDowall, A. & Hogg, N. The integrin LFA-1 signals through ZAP-70 to regulate expression of high-affinity LFA-1 on T lymphocytes. Blood 117, 3331–3342 (2011).

    CAS  Article  Google Scholar 

  16. Weber, C., Kreuter, J. & Langer, K. Desolvation process and surface characteristics of HSA-nanoparticles. Int. J. Pharm. 196, 197–200 (2000).

    CAS  Article  Google Scholar 

  17. Sumagin, R., Prizant, H., Lomakina, E., Waugh, R. E. & Sarelius, I. H. LFA-1 and Mac-1 define characteristically different intralumenal crawling and emigration patterns for monocytes and neutrophils in situ. J. Immunol. 185, 7057–7066 (2010).

    CAS  Article  Google Scholar 

  18. Bull, H. B. & Breese, K. Interaction of alcohols with proteins. Biopolymers 17, 2121–2131 (1978).

    CAS  Article  Google Scholar 

  19. Wang, Z., Tiruppathi, C., Minshall, R. D. & Malik, A. B. Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. ACS Nano 3, 4110–4116 (2009).

    CAS  Article  Google Scholar 

  20. Chen, K. et al. Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo. Blood 120, 4421–4431 (2012).

    CAS  Article  Google Scholar 

  21. Indik, Z. K., Park, J. G., Hunter, S. & Schreiber, A. D. The molecular dissection of Fcγ receptor mediated phagocytosis. Blood 86, 4389–4399 (1995).

    CAS  Google Scholar 

  22. Zarbock, A., Lowell, C. A. & Ley, K. Spleen tyrosine kinase Syk is necessary for E-selectin-induced αLβ2 integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 26, 773–783 (2007).

    CAS  Article  Google Scholar 

  23. Geahlen, R. L. & McLaughlin, J. L. Piceatannol (3,4,3′,5′-tetrahydroxy-trans-stilbene) is a naturally occurring protein-tyrosine kinase inhibitor. Biochem. Biophys. Res. Commun. 165, 241–245 (1989).

    CAS  Article  Google Scholar 

  24. Wisel, S. et al. Pharmacological preconditioning of mesenchymal stem cells with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine) protects hypoxic cells against oxidative stress and enhances recovery of myocardial function in infarcted heart through Bcl-2 expression. J. Pharmacol. Exp. Ther. 329, 543–550 (2009).

    CAS  Article  Google Scholar 

  25. Matthay, M. A. & Zemans, R. L. The acute respiratory distress syndrome: pathogenesis and treatment. Annu. Rev. Pathol. 6, 147–163 (2011).

    CAS  Article  Google Scholar 

  26. Lo, S. K., Everitt, J., Gu, J. & Malik, A. B. Tumor necrosis factor mediates experimental pulmonary edema by ICAM-1 and CD18-dependent mechanisms. J. Clin. Invest 89, 981–988 (1992).

    CAS  Article  Google Scholar 

  27. Nakatani, K. et al. Regulation of the expression of Fcγ receptor on circulating neutrophils and monocytes in Kawasaki disease. Clin. Exp. Immunol. 117, 418–422 (1999).

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by grant no. 11SDG7490013 from the American Heart Association and National Institutes of Health grants K25HL111157 to Z.W., R01 HL109439 to J.C. and P01 P01HL77806 to A.B.M.

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Z.W., J.C. and A.B.M. designed the experiments and analysed the data. Z.W. and J.L. carried out the experiments. Z.W., J.C. and A.B.M. wrote the manuscript.

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Correspondence to Asrar B. Malik.

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The authors declare no competing financial interests.

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Wang, Z., Li, J., Cho, J. et al. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nature Nanotech 9, 204–210 (2014). https://doi.org/10.1038/nnano.2014.17

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