- Open Access
Cutaneous exposure to agglomerates of silica nanoparticles and allergen results in IgE-biased immune response and increased sensitivity to anaphylaxis in mice
- Toshiro Hirai1,
- Yasuo Yoshioka1, 2, 3Email author,
- Hideki Takahashi1, 2,
- Ko-ichi Ichihashi1,
- Asako Udaka1,
- Takahide Mori4,
- Nobuo Nishijima1,
- Tokuyuki Yoshida1,
- Kazuya Nagano5,
- Haruhiko Kamada5, 6,
- Shin-ichi Tsunoda5, 6,
- Tatsuya Takagi7, 8,
- Ken J. Ishii9, 10,
- Hiromi Nabeshi11,
- Tomoaki Yoshikawa1,
- Kazuma Higashisaka1, 5 and
- Yasuo Tsutsumi1, 4, 6Email author
© Hirai et al. 2015
Received: 18 April 2015
Accepted: 16 June 2015
Published: 26 June 2015
The skin is a key route of human exposure to nanomaterials, which typically occurs simultaneously with exposure to other chemical and environmental allergen. However, little is known about the hazards of nanomaterial exposure via the skin, particularly when accompanied by exposure to other substances.
Repeated topical treatment of both ears and the shaved upper back of NC/Nga mice, which are models for human atopic dermatitis (AD), with a mixture of mite extract and silica nanoparticles induced AD-like skin lesions. Measurements of ear thickness and histologic analyses revealed that cutaneous exposure to silica nanoparticles did not aggravate AD-like skin lesions. Instead, concurrent cutaneous exposure to mite allergens and silica nanoparticles resulted in the low-level production of allergen-specific IgGs, including both the Th2-related IgG1 and Th1-related IgG2a subtypes, with few changes in allergen-specific IgE concentrations and in Th1 and Th2 immune responses. In addition, these changes in immune responses increased the sensitivity to anaphylaxis. Low-level IgG production was induced when the mice were exposed to allergen–silica nanoparticle agglomerates but not when the mice exposed to nanoparticles applied separately from the allergen or to well-dispersed nanoparticles.
Our data suggest that silica nanoparticles themselves do not directly affect the allergen-specific immune response after concurrent topical application of nanoparticles and allergen. However, when present in allergen-adsorbed agglomerates, silica nanoparticles led to a low IgG/IgE ratio, a key risk factor of human atopic allergies. We suggest that minimizing interactions between nanomaterials and allergens will increase the safety of nanomaterials applied to skin.
Because of their unique features and physicochemical properties [1, 2], nanomaterials are increasingly being used to add value to new and existing goods, such as cosmetics, foods, medicines, and industrial products [3–5]. However, these same novel features of nanomaterials make them hazardous under some conditions [6, 7]. To take full advantage of the potential benefits of nanomaterials, we must learn more about their hazards so that safer nanomaterials can be designed.
Numerous epidemiologic studies have prompted concerns regarding the health risks associated with exposure to nanomaterials; in particular, such studies have revealed that exposure to particulate matter (PM), including PM2.5 and Asian dust, induces many adverse effects, including facilitating the onset and severity of allergic diseases [8–11]. Because inhalational exposure to PM has been considered to be the main inducer of these adverse effects, this route has received the most attention regarding exposure to nanomaterials . However, the skin is a major route of both intentional (from clothing, cosmetics, and other skin care products) and unintentional (from the environment) exposure to nanomaterials [13–15]. Furthermore, exposure to nanomaterials often occurs simultaneously with exposure to other chemical compounds and environmental allergens , but little is known about the hazards of cutaneous exposure to nanomaterials, particularly in combination with other substances.
In the current study, we investigated the effects of concurrent topical application of mite extract and amorphous silica nanoparticles, one of the most widely used nanomaterials, on allergic sensitization and AD in NC/Nga mice, a murine model of AD. We found that cutaneous exposure to the allergen and silica nanoparticles simultaneously did not aggravate AD-like skin lesions in the mice but resulted in low-level IgG production with little change in IgE production (IgE-biased immune response) and increased sensitivity to anaphylaxis. We suggest that an IgE-biased immune response was induced independently of the innate biologic effects of silica nanoparticles. Because a low IgG/IgE ratio is a characteristic feature of human atopic allergy, we believe that minimizing interactions between nanomaterials and allergens may improve the safety of cutaneously applied nanomaterials.
Results and discussion
Effects of co-exposure to mite allergen and silica nanoparticles in a murine model of AD
Total IgE levels in plasma, which are often elevated in AD and other allergic conditions , were measured 24 h after the final treatment. The total IgE level in the Dp-alone group was higher than that in the PBS group (Fig. 2f), and the total IgE level in the Dp + nSP30 group was slightly higher than that in the Dp-alone group (Fig. 2f). Because a Th2-mediated immune response including IgE production is unnecessary for the development of AD-like skin lesions in NC/Nga mice , the high total IgE level induced by cutaneous exposure to Dp + nSP30 likely did not exacerbate the Dp-induced AD-like skin lesions in NC/Nga mice.
Effect of cutaneous exposure to Dp + nSP30 on cutaneous allergic sensitization
To further characterize the systemic immune responses, we enumerated the Dp-specific splenocytes secreting interferon-γ (IFN-γ) and interleukin-4 (IL-4) in each mouse by using cytokine-specific enzyme-linked immunosorbent spot (ELISPOT) assays (Fig. 3d). The numbers of Dp-specific IFN-γ- and IL-4-secreting splenocytes did not differ between the Dp-alone group and the Dp + nSP30 group. In addition, although concentration of IL-21 in the supernatants of splenocytes was significantly lower in the Dp + nSP30 group than in the Dp-alone group, none of the other measured cytokines (IL-5, 10, 13, and 17) differed between these groups (Additional file 3). Therefore, nSP30 might have affected IgG production without altering systemic Th1 and Th2 immune responses. Because IL-21 is a critical factor in IgG production [24, 25], additional study of IL-21 likely would help to clarify the mechanism underlying the reductions in both the IgG1 and IgG2a subtypes.
Recently, the skin was revealed to be the key initial site of allergic sensitization not only for allergic eczema but also for other atopic allergies, including allergic rhinitis, asthma, and food allergies [26–28]. Therefore, skin might play a special role in allergic sensitization. To this end, we assessed the effects of exposure to Dp + nSP30 by various other exposure routes on the IgG response (Additional file 4). Consistent with our previously reported results , nSP30-mediated IgG suppression was not observed after intranasal, oral, or intradermal administration of Dp + nSP30, thus suggesting that the low IgG response was a specific effect induced by cutaneous exposure to Dp + nSP30.
Effect of cutaneous exposure to Dp + nSP30 on susceptibility to anaphylaxis
Effects of sequential cutaneous exposure to allergen and nSP30 on the IgE-biased immune response
Effects of agglomeration of allergen and nSP30 on the IgE-biased immune response
We previously examined the Dp dose-effect in the same NC/Nga model (Hirai T. et al., submitted paper). In that study, levels of both Dp-specific IgE and IgG were correlated with exposure amount of Dp in the range of 30 to 120 μg Dp mouse−1; in the current study, we used a dose of 120 μg Dp mouse−1 for the Dp-alone group. Furthermore, the Th2-related cytokine response in Dp-stimulated splenocytes was lower in the120-μg Dp mouse−1 group than in other (lower) dose groups. In contrast, we show here that the exposure to agglomerates of Dp and nSP30 in PBS induced a dampened Dp-specific IgG response with little change in the Dp-specific IgE and Th1/Th2 immune responses compared with those of the Dp-alone group (Fig. 3 and Additional file 3). Together, these observations suggest that the IgE-biased immune response in the current study was not solely due to the low Dp exposure resulting from the agglomeration of Dp and nSP30. Perhaps the agglomerates of Dp and nSP30 in PBS not only decreased the Dp exposure dose but also behaved as a ‘depot,’ thus controlling the allergen concentration, prolonging allergen exposure, and subsequently causing IgE-biased allergic sensitization. We believe additional studies that focus on the effect of nanoparticles on allergen penetration kinetics in the skin would be beneficial to confirm the safety of cutaneous exposure to nanomaterials. However, we acknowledge the need for additional studies in which the exposure scenario is more representative of that in humans to define the safety of concurrent cutaneous exposure to nanomaterials and allergen.
It is well recognized that there are some situations in our daily lives, the development of atopic allergy is inhibited by higher dose exposure to allergen due to high induction of blocking IgG [46–48]. Particularly in these high-dose exposure situations, we suggest that allergen-nanoparticle agglomerates, by inducing IgE-biased immune responses, might play a critical role in the development of atopic allergy. In addition, the IgE-biased immune response induced by cutaneous exposure to agglomerates of allergen and nanoparticles in our mice was similar to those humans with atopic allergies, who often have a low IgG/IgE ratio, as mentioned earlier [40, 41]. Therefore epidemiologic studies that address cutaneous as well as inhalational exposure to nanomaterials may improve our understanding of the onset of atopic allergy.
Recently, Ilves M. et al. described the effects of cutaneous exposure to nano-sized ZnO (nZnO) administered with model antigens, ovalbumin and staphylococcal enterotoxin B, on AD-like skin lesions and antibody responses . Interestingly, the effects observed for nZnO and an antigen were similar to the effects of agglomerates of Dp and nSP30: nZnO suppressed allergen-induced skin inflammation and induced low-level IgG production in the context of a high IgE response. The authors of the previous study  did not address changes of nZnO dispersibility by mixing allergen, but considering that nZnO is predisposed to forming agglomerates and might adsorb a coexisting substance , nZnO might play similar role to that of nSP30. To better understand the hazards of nanomaterials so that we can maximize their potential benefits, we should pay increased attention to the state of nanoparticles (e.g. dispersibility) in administration in nanotoxicology studies. We consider this focus particularly applicable in the hazard evaluation of nanomaterials that are in the presence of other substances, which could interact with them.
Cutaneous exposure to aggregates or agglomerates of nanomaterials is generally considered to be safer than is similar exposure to individual nanoparticles, mainly because agglomerates of nanomaterials have difficulty penetrating the skin . However, Dp and nSP30 induced an IgE-biased immune response only when they formed agglomerates. Although these results represent only indirect effects of nanomaterials, we think that hazard identification is necessary even when nanomaterials are considered to be unable to cross the skin barrier (e.g. when nanomaterials form aggregates or agglomerates). In contrast, surface modification of the nSP30 with carboxyl groups suppressed the adsorption of the allergen and did not induce IgE-biased allergic sensitization (Fig. 6). An increased understanding of the regulatory factors that induce the agglomeration of silica nanoparticles is crucial for appropriate regulation of the surface properties of nanomaterials so that they can be used safely.
Cutaneous exposure to agglomerates of Dp and nSP30 induced an IgE-biased immune response in NC/Nga mice and increased their sensitivity to anaphylaxis. Surprisingly, these results were independent of the innate biologic effects of nSP30; these results required both simultaneous exposure to Dp and nSP30 and their agglomeration. In particular, features of the mice with IgE-biased immune response induced by cutaneous exposure to agglomerates of allergen and nanoparticles resembled those of humans with atopic allergies, who often have a low IgG/IgE ratio; follow-up epidemiologic studies that focus cutaneous compared with inhalational exposure to nanomaterials might improve our understanding of the onset of atopic allergy. In light of our findings, we suggest that minimizing the interaction between nanomaterials and allergens may improve the safety of topically applied products containing nanomaterials.
nSP30 and nSP30C (nSP30C is a surface modified nSP30 with carboxyl groups) silica nanoparticles (diameter, 30 mm) were purchased from Micromod Partikeltechnologie (Rostock/Warnemünde, Germany). Suspensions of silica nanoparticles were stored at room temperature. Immediately prior to use, the suspensions were sonicated at 400 W for 5 min at 25 °C and then vortexed for 1 min.
Female NC/Nga slc mice were purchased from SLC (Kyoto, Japan) and used at 6 wk of age. All animal experiments were performed in accordance with the institutional guidelines of Osaka University and National Institute of Biomedical Innovation regarding the ethical treatment of animals.
Preparation of the mixtures of Dp and nSP30s
To prepare the mixtures of nSP30s and Dp (Cosmo Bio LSL, Tokyo, Japan), we first combined nSP30s (25 mg mL−1 in water) and concentrated PBS (1.1× to 4.6×; the concentration of the PBS stock used depended on the concentration of nSP30s needed in the final sample, the diluent for which was 1× PBS). We then added the stock solution of Dp (2.78 mg protein mL−1 in PBS) to the solutions containing various concentrations of nSP30s. As soon as the nSP30s and Dp solutions were combined, the mixtures were vortexed for 1 min, allowed to incubate at room temperature for 0.5 to 1.5 h, and vortexed again for 1 min just prior to use.
Physicochemical examination of silica nanoparticles
TEM (H-7650; Hitachi High-Technologies Corporation, Tokyo, Japan) was used to assess the size and shape of the silica nanoparticles. nSP30 and nSP30C nanoparticles were diluted to 0.25 mg mL−1 in PBS or deionized water, and the mean particle diameter and zeta potential at 25 °C were measured by using a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Specifically, the mean diameters and particle size distributions of the nanoparticles were measured by means of a dynamic light-scattering method, whereas zeta potentials were measured by laser Doppler electrophoresis; both types of measurements were performed by using capillary cells (Malvern Instruments). The pH of each particle suspension was measured by using an ISFET pH meter (Shindengen, Tokyo, Japan).
Skin painting and assessment of allergic response
Using a hair-removal cream (Epilat; Kracie, Tokyo, Japan), we removed the hair from the backs of all mice twice during each experiment (on day 1 and on day 18–20). Mice were treated either with Dp (1 mg mL−1 fin. conc) alone or with silica nanoparticles (nSP30 or nSP30C, 12.5 mg mL−1 fin. conc.) in 120 μL PBS by painting the ventral side of both ears and the depiliated dorsum (20 μL per ear and 80 μL on the back) on alternate days or every third day for 4 wk for a total of 13 applications. Additional mice were painted with Dp only on one day followed by painting with nSP30 alone on the next day; this alternating pattern was repeated for a total of 13 applications of each solution over 4 wk. Regardless of the dose schedule used, any sample remaining from a previous application was removed by gently wiping with a disposable wipe (Kim wipes, Crecia, Tokyo, Japan) wetted with 70 % ethanol.
We used a dial thickness gauge (0.001-mm type; Ozaki Manufacturing, Tokyo, Japan) to measure ear thickness weekly. To evaluate the severity of the IgE-mediated allergic response’ instead, we used a systemic anaphylaxis model. Specifically, at 1 wk after the final skin painting, each mouse was challenged with an intravenous injection of Dp (15 μg in 200 μL PBS). The severity of anaphylactic shock was assessed according to the change in rectal temperature measured by using a digital thermometer (KN-91; Natsume Seisakusho, Tokyo, Japan).
At 24 h after the final topical treatment, the ears of euthanized mice were removed, placed in fixative solution (4 % paraformaldehyde in PBS; Wako, Osaka, Japan), embedded in paraffin, and sectioned. The tissue sections were stained with hematoxylin and eosin or with toluidine blue. Histopathological examination was performed by the Applied Medical Research Laboratory (Osaka, Japan). For each sample, representative symptoms of AD (scab formation, acanthosis and inflammatory cell infiltration) were scored as follows: 0, none; 1, slight; 2, mild; 3, moderate; and 4, severe. In addition, we counted the number of mast cells in 3 random high-power fields (magnification, 400×).
Using hematocrit capillary tubes (Terumo, Tokyo, Japan), we obtained blood samples from the retro-orbital venous plexus once each week during the study period. At 24 h after the final skin painting, blood was collected by cardiocentesis into heparin-treated syringes and centrifuged at 3000 × g at 4 °C; the resulting plasma was stored at −80 °C until analysis.
Quantitation of total IgE concentration
The total IgE concentration in plasma was measured by using an ELISA kit (BD Biosciences, San Diego, CA, USA) according to the manufacturer’s instructions.
Detection of Dp-specific antibody
The levels of Dp-specific antibody in plasma were determined by ELISA. To detect IgG, IgG1, IgG2a, IgG2b and IgG3, we coated ELISA plates (Maxisorp, type 96 F; Nunc A/S, Roskilde, Denmark) with Dp in PBS (50 μg mL−1). The coated plates were incubated with 2 % Block Ace (Dainippon Sumitomo Pharmaceuticals, Osaka, Japan). Plasma samples were diluted by 2 % Block Ace and these dilutions were added to the Dp-coated plates. After incubation with plasma, the coated plates were incubated with a horseradish peroxidase–conjugated goat anti-mouse IgG, IgG1, IgG2a, IgG2b or IgG3 solution (SouthernBiotech, Birmingham, AL, USA) for two hours at room temperature. After the incubation, the color reaction was developed with tetramethyl benzidine (Moss, Inc.; Pasadena, MD, USA), stopped with 2 N H2SO4, and measured at OD450–620 on a microplate reader.
To detect Dp-specific IgE, we coated ELISA plates (Maxisorp, type 96 F) with purified rat anti-mouse IgE (2 μg mL−1; R35-72, BD Biosciences;), incubated them with Block Ace, and added samples of diluted plasma as described earlier. Treated plates were incubated with biotin-conjugated Dp (5 μg mL−1) followed by horseradish peroxidase–coupled streptavidin (Southern Biotechnology Associates). Color detection was performed as described earlier.
Isolation of splenocytes
Spleens were removed aseptically and placed in RPMI 1640 (Wako) supplemented with 10 % fetal bovine serum, 10 mL L−1 of a 100× nonessential amino acid solution (Gibco, Invitrogen, Carlsbad, CA, USA), 50 μM 2-mercaptoethanol (Gibco), and 1 % antibiotic cocktail (10,000 U mL−1 penicillin, 10,000 μg mL−1 streptomycin, 25 μg mL−1 amphotericin B; Gibco). Single-cell suspensions of splenocytes were treated with ammonium chloride to lyse the red blood cells; treated splenocytes then were washed, counted, and suspended in RPMI 1640.
To determine antigen-specific cytokine (IFN-γ and IL-4) responses, splenocytes (5 × 105 cells well−1) were stimulated with Dp antigen (100 μg mL−1) in vitro. After 24 h incubation at 37 °C (95 % room air, 5 % CO2), stimulated splenocytes were washed, and the numbers of IFN-γ- and IL-4-producing cells were determined by using an ELISPOT assay kit (BD Biosciences) according to the manufacturer’s instructions.
Measurement of amount of Dp adsorbed to silica nanoparticles
Solutions of Dp (1 mg mL−1 fin. conc.) + each nSP immediately after preparation in PBS or water for 30 min at 25 °C were centrifuged (2 h, 40,000 × g, 4 °C). The amount of Dp in the supernatant then was determined spectrophotometrically (OD280; Nanodrop 2000, Thermo Scientific, Kanagawa, Japan).
Statistical analyses were performed with Ekuseru-Toukei 2010 software (Social Survey Research Information Co., Ltd., Tokyo, Japan). All data are presented as means ± SEMs. Significant differences between control groups and experimental groups were determined by using the Dunnett test; a P value less than 0.05 was considered significant.
Methods for additional files are available in (Additional file 5).
This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and from the Japan Society for the Promotion of Science (JSPS); by a Grant-in-Aid for JSPS Fellows; by Health Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (MHLW); by The Takeda Science Foundation; by The Research Foundation for Pharmaceutical Sciences; by The Japan Food Chemical Research Foundation; by the Urakami Foundation; and by the Uehara Memorial Foundation.
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