Inert 50-nm Polystyrene Nanoparticles That Modify Pulmonary Dendritic Cell Function and Inhibit Allergic Airway Inflammation

Abstract

Nanoparticles are being developed for diverse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c+MHCIIhi DCs in the lung and draining LN and allergen-laden CD11bhiMHCIIhi DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11bhi DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4+ T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.

Differential Uptake of Nanoparticles and Microparticles by Pulmonary APC Subsets Induces Discrete Immunological Imprints

“…1C). The peak PS50G-induced increases in lung and LN cell counts were ∼2-fold lower than those seen during acute AAI (11,25).…”

“…OVA challenge (25 mg) on days 32, 34, 37, and 39 as described (Fig. 10A) (11). In experiments to test particle effects on allergen uptake, mice received particles i.t.…”

“…For differentials, BAL cytospots were Giemsa stained (Merck, Kilsyth, VIC, Australia) and $200 cells identified by morphological criteria. Tissue digestion was performed as described previously (11). The right ventricle was perfused with 5 ml Ca 2+ /Mg 2+ -free HBSS (Invitrogen; #14175095) with 0.01 M EDTA (pH 7.2).…”

“…PS500G microparticles induced a smaller expansion in BAL cell numbers at day 1, returning to baseline by day 31. To put these particle-induced increases in context, BAL counts in acute AAI (11,25) are typically 6-10-fold greater (3-5 3 10 6 cells) than the maximum values seen in PS50G-treated mice. PS50G nanoparticles caused an ∼2-fold increase in lung leukocyte counts relative to controls at all time points (Fig.…”

“…Similarly, man-made carbon black and titanium dioxide nanoparticles (6)(7)(8) and carbon nanotubes (9,10) all promote allergic sensitization and/or allergic airway inflammation (AAI). However, counterintuitively, we recently made the discovery that preadministration of inert nontoxic polystyrene nanoparticles 50 nm in diameter (PS50G), which do not induce oxidative stress, can inhibit development of AAI by impairing pulmonary dendritic cell (DC) expansion or stimulatory function (11). It is currently unknown if the novel beneficial immunological imprint of particle exposure in the lung that we identified using PS50G is affected by particle size.…”