Immune Toxicity of and Allergic Responses to Nanomaterials

  • Yasuo YoshiokaEmail author
  • Toshiro Hirai
  • Yasuo Tsutsumi
Part of the Current Topics in Environmental Health and Preventive Medicine book series (CTEHPM)


Over the past decade, the remarkable development of nanomaterials and nanotechnology has led to their use in many applications. But as the uses of nanomaterials have increased, so have concerns regarding their potential adverse effects (that is, nanotoxicity) in humans and the environment. Because the body’s immune systems are responsible for dealing with foreign substances, we likely should expect at least some interaction of nanomaterials with our immune systems with daily use of nanomaterials, and we must understand those interactions in order to use nanomaterials safely or to develop safer nanomaterials. In this review, we summarize recent advances in immunotoxicology studies of nanomaterials, especially (1) macrophage recognition of nanomaterials with particular emphasis on the effect of particle size, and (2) in vivo responses after skin exposure to nanomaterials, including the onset or aggravation of allergy. In addition, we discuss challenges to further understanding the immune system–nanomaterial interaction, with the goal of increasing the safety of these compounds.


Allergy Cytokine Nanomaterial Nanotoxicity Macrophage Skin 


  1. 1.
    Pietroiusti A, et al. Nanomaterial exposure, toxicity, and impact on human health. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2018;10(5):e1513.Google Scholar
  2. 2.
    Geiser M, Kreyling WG. Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol. 2010;7:2.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Yamashita K, et al. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol. 2011;6(5):321–8.PubMedGoogle Scholar
  4. 4.
    Morishita Y, et al. Distribution of silver nanoparticles to breast Milk and their biological effects on breast-fed offspring mice. ACS Nano. 2016;10(9):8180–91.PubMedGoogle Scholar
  5. 5.
    Liao HY, et al. Sneezing and allergic dermatitis were increased in engineered nanomaterial handling workers. Ind Health. 2014;52(3):199–215.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Wu WT, et al. Effect of nanoparticles exposure on fractional exhaled nitric oxide (FENO) in workers exposed to nanomaterials. Int J Mol Sci. 2014;15(1):878–94.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Alsaleh NB, Brown JM. Immune responses to engineered nanomaterials: current understanding and challenges. Curr Opin Toxicol. 2018;10:8–14.PubMedGoogle Scholar
  8. 8.
    Fadeel B. Hide and Seek: nanomaterial interactions with the immune system. Front Immunol. 2019;10:133.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Canton J, et al. Scavenger receptors in homeostasis and immunity. Nat Rev Immunol. 2013;13(9):621–34.PubMedGoogle Scholar
  10. 10.
    Kanno S, et al. A murine scavenger receptor MARCO recognizes polystyrene nanoparticles. Toxicol Sci. 2007;97(2):398–406.PubMedGoogle Scholar
  11. 11.
    Lara S, et al. Differential recognition of nanoparticle protein Corona and modified low-density lipoprotein by macrophage receptor with collagenous structure. ACS Nano. 2018;12(5):4930–7.PubMedGoogle Scholar
  12. 12.
    Gallud A, et al. Macrophage activation status determines the internalization of mesoporous silica particles of different sizes: exploring the role of different pattern recognition receptors. Biomaterials. 2017;121:28–40.PubMedGoogle Scholar
  13. 13.
    Tsugita M, et al. SR-B1 is a silica receptor that mediates canonical Inflammasome activation. Cell Rep. 2017;18(5):1298–311.PubMedGoogle Scholar
  14. 14.
    Thakur SA, et al. Role of scavenger receptor a family in lung inflammation from exposure to environmental particles. J Immunotoxicol. 2008;5(2):151–7.PubMedGoogle Scholar
  15. 15.
    Yamashita T, et al. Carbon Nanomaterials: efficacy and safety for Nanomedicine. Materials (Basel). 2012;5(2):350–63.Google Scholar
  16. 16.
    Morishige T, et al. Suppression of nanosilica particle-induced inflammation by surface modification of the particles. Arch Toxicol. 2012;86(8):1297–307.PubMedGoogle Scholar
  17. 17.
    Nishijima N, et al. Human scavenger receptor A1-mediated inflammatory response to silica particle exposure is size specific. Front Immunol. 2017;8:379.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Handa T, et al. Identifying a size-specific hazard of silica nanoparticles after intravenous administration and its relationship to the other hazards that have negative correlations with the particle size in mice. Nanotechnology. 2017;28(13):135101.PubMedGoogle Scholar
  19. 19.
    Jiang W, et al. Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol. 2008;3(3):145–50.PubMedGoogle Scholar
  20. 20.
    Lu F, et al. Size effect on cell uptake in well-suspended, uniform mesoporous silica nanoparticles. Small. 2009;5(12):1408–13.PubMedGoogle Scholar
  21. 21.
    Jones SW, et al. Nanoparticle clearance is governed by Th1/Th2 immunity and strain background. J Clin Invest. 2013;123(7):3061–73.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Hoppstadter J, et al. M2 polarization enhances silica nanoparticle uptake by macrophages. Front Pharmacol. 2015;6:55.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Sun B, et al. NLRP3 inflammasome activation induced by engineered nanomaterials. Small. 2013;9(9–10):1595–607.PubMedGoogle Scholar
  24. 24.
    Yazdi AS, et al. Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1alpha and IL-1beta. Proc Natl Acad Sci U S A. 2010;107(45):19449–54.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Sun B, et al. NADPH oxidase-dependent NLRP3 Inflammasome activation and its important role in lung fibrosis by multiwalled carbon nanotubes. Small. 2015;11(17):2087–97.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Gasse P, et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007;117(12):3786–99.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Reisetter AC, et al. Induction of inflammasome-dependent pyroptosis by carbon black nanoparticles. J Biol Chem. 2011;286(24):21844–52.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Aoyama M, et al. Intracellular trafficking of particles inside endosomal vesicles is regulated by particle size. J Control Release. 2017;260:183–93.PubMedGoogle Scholar
  29. 29.
    Nakayama M. Macrophage recognition of crystals and nanoparticles. Front Immunol. 2018;9:103.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Boraschi D, et al. Nanoparticles and innate immunity: new perspectives on host defence. Semin Immunol. 2017;34:33–51.PubMedGoogle Scholar
  31. 31.
    Wang M, et al. Evaluation of immunoresponses and cytotoxicity from skin exposure to metallic nanoparticles. Int J Nanomedicine. 2018;13:4445–59.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–9.PubMedGoogle Scholar
  33. 33.
    Yoshioka Y, et al. Allergic responses induced by the Immunomodulatory effects of Nanomaterials upon skin exposure. Front Immunol. 2017;8:169.PubMedPubMedCentralGoogle Scholar
  34. 34.
    van Loveren H, et al. Skin sensitization in chemical risk assessment: report of a WHO/IPCS international workshop focusing on dose-response assessment. Regul Toxicol Pharmacol. 2008;50(2):155–99.PubMedGoogle Scholar
  35. 35.
    Lalko JF, et al. Chemical reactivity measurements: potential for characterization of respiratory chemical allergens. Toxicol In Vitro. 2011;25(2):433–45.PubMedGoogle Scholar
  36. 36.
    Park YH, et al. Analysis for the potential of polystyrene and TiO2 nanoparticles to induce skin irritation, phototoxicity, and sensitization. Toxicol In Vitro. 2011;25(8):1863–9.PubMedGoogle Scholar
  37. 37.
    Lee S, et al. The comparative effects of mesoporous silica nanoparticles and colloidal silica on inflammation and apoptosis. Biomaterials. 2011;32(35):9434–43.PubMedGoogle Scholar
  38. 38.
    Ilves M, et al. Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model. Part Fibre Toxicol. 2014;11:38.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Chen BX, et al. Antigenicity of fullerenes: antibodies specific for fullerenes and their characteristics. Proc Natl Acad Sci U S A. 1998;95(18):10809–13.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hirai T, et al. Metal nanoparticles in the presence of lipopolysaccharides trigger the onset of metal allergy in mice. Nat Nanotechnol. 2016;11(9):808–16.PubMedGoogle Scholar
  41. 41.
    Wiesner MR, et al. Meditations on the ubiquity and mutability of nano-sized materials in the environment. ACS Nano. 2011;5(11):8466–70.PubMedGoogle Scholar
  42. 42.
    Hirai T, et al. Cutaneous exposure to agglomerates of silica nanoparticles and allergen results in IgE-biased immune response and increased sensitivity to anaphylaxis in mice. Part Fibre Toxicol. 2015;12:16.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Hirai T, et al. High-dose cutaneous exposure to mite allergen induces IgG-mediated protection against anaphylaxis. Clin Exp Allergy. 2016;46(7):992–1003.PubMedGoogle Scholar
  44. 44.
    Deng ZJ, et al. Nanoparticle-induced unfolding of fibrinogen promotes mac-1 receptor activation and inflammation. Nat Nanotechnol. 2011;6(1):39–44.PubMedGoogle Scholar
  45. 45.
    Aoyama M, et al. Clusterin in the protein corona plays a key role in the stealth effect of nanoparticles against phagocytes. Biochem Biophys Res Commun. 2016;480(4):690–5.PubMedGoogle Scholar
  46. 46.
    Lara S, et al. Identification of receptor binding to the biomolecular Corona of nanoparticles. ACS Nano. 2017;11(2):1884–93.PubMedGoogle Scholar
  47. 47.
    Hirai T, et al. Potential suppressive effects of two C60 fullerene derivatives on acquired immunity. Nanoscale Res Lett. 2016;11(1):449.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Huaux F. Emerging role of immunosuppression in diseases induced by micro- and Nano-particles: time to revisit the exclusive inflammatory scenario. Front Immunol. 2018;9:2364.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Tsugita M, et al. SiO2 and TiO2 nanoparticles synergistically trigger macrophage inflammatory responses. Part Fibre Toxicol. 2017;14(1):11.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Brodin P, Davis MM. Human immune system variation. Nat Rev Immunol. 2017;17(1):21–9.PubMedGoogle Scholar
  51. 51.
    Fadeel B, et al. Advanced tools for the safety assessment of nanomaterials. Nat Nanotechnol. 2018;13(7):537–43.PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Yasuo Yoshioka
    • 1
    • 2
    • 3
    • 4
    Email author
  • Toshiro Hirai
    • 5
  • Yasuo Tsutsumi
    • 4
    • 6
  1. 1.BIKEN Innovative Vaccine Research Alliance LaboratoriesResearch Institute for Microbial Diseases, Osaka UniversityOsakaJapan
  2. 2.BIKEN Center for Innovative Vaccine Research and DevelopmentThe Research Foundation for Microbial Diseases of Osaka UniversityOsakaJapan
  3. 3.Laboratory of Nano-Design for Innovative Drug Development, Graduate School of Pharmaceutical SciencesOsaka UniversityOsakaJapan
  4. 4.The Center for Advanced Medical Engineering and InformaticsOsaka UniversityOsakaJapan
  5. 5.Departments of Dermatology and ImmunologyUniversity of PittsburghPittsburghUSA
  6. 6.Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical SciencesOsaka UniversityOsakaJapan

Personalised recommendations