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. 2017 Feb 27:7:43586.
doi: 10.1038/srep43586.

TRPA1 mediated aggravation of allergic contact dermatitis induced by DINP and regulated by NF-κB activation

Jun Kang  1 , Yong Ding  2 , Baizhan Li  2 , Hong Liu  2 , Xu Yang  1 , Mingqing Chen  1
Affiliations

TRPA1 mediated aggravation of allergic contact dermatitis induced by DINP and regulated by NF-κB activation

Jun Kang et al. Sci Rep. .

Abstract

The possible pathogenic role and mechanism of Di-iso-nonyl phthalate (DINP) in allergic dermatitis is still controversial. This work has shown that oral exposure to DINP exacerbated allergic dermatitis tissue lesions in FITC-sensitized mice. The lesions was accompanied by an enhancement of TRPA1 expression and an increase in IgG1, IL-6 and IL-13 levels. This work also found that blocking TRPA1 by HC030031 effectively prevented the development of allergic dermatitis resulting from oral exposure to DINP and/or FITC-sensitized mice. This result is marked by the down regulation of IgG1 levels, a reduction in mast cell degranulation and a decrease in IL-6 and IL-13 levels. We also showed that blocking NF-κB inhibited TRPA1 expression, and that blocking TRPA1 had no significant effect on the activation of NF-κB or TSLP expression. This study helps in understanding the role DINP exposure plays in the development of allergic dermatitis and provides new insight into the mechanisms behind the DINP-induced adjuvant effect.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. DINP exacerbated expression of TRPA1 and HC030031 inhibited this effect.
(A) The expression levels of TRPA1 mRNA. (B) Immunohistochemistry for TRPA1. (C) The expression scores of TRPA1. *p < 0.05, **p < 0.01, compared with saline group. NS, no significant difference, &p < 0.05, &&p < 0.01 compared with FITC group. ##p < 0.01, FITC + DINP200 group versus FITC + DINP200 + HC030031 group. (n = 7). Saline group, mice were gavaged with saline for 3 weeks, then sensitized and challenged with saline and vehicle; DINP200 group, mice were gavaged with 200 mg/(kg·d) of DINP for 3 weeks, then sensitized and challenged with saline and vehicle saline; FITC group, mice were gavaged with saline for 3 weeks, then sensitized and challenged with 0.5% FITC; FITC + HC030031 group, mice were gavaged with saline for 3 weeks, on days 22, 23 and 28, HC030031 was injected (50 mg/kg, i.p.) before sensitization and challenge with 0.5% FITC; FITC + DINP2, FITC + DINP20, FITC + DINP200 groups, mice were gavaged with 2, 20 and 200 mg/(kg·d) dose of DINP for 3 weeks, then sensitized and challenged with 0.5% FITC; FITC + DINP200 + HC030031 group, mice were gavaged with 200 mg/(kg·d) dose of DINP for 3 weeks, on days 22, 23 and 28, HC030031 was injected (50 mg/kg, i.p.) before sensitization and challenge with 0.5% FITC.
Figure 2
Figure 2
Blockade of TRPA1 alleviated allergic contact dermatitis aggravated by DINP (A) The skin from the exposed back of mice, stained with hematoxylin & eosin (H&E). A1, saline group. A2, DINP200 group. A3, FITC group. A4, FITC + HC030031 group. A5-A7, FITC + DINP2, FITC + DINP20, FITC + DINP200 groups. (B) Number of inflammatory cells infiltrating the skin. (C) Ratio of neutrophils in the peripheral blood. (D) Total IgE concentrations (ng/ml). *p < 0.05, **p < 0.01, compared with saline group. NS, no significant difference, &p < 0.05, &&p < 0.01 compared with FITC group. ##p < 0.01, FITC + DINP200 group versus FITC + DINP200 + HC030031 group. (n = 7).
Figure 3
Figure 3. Blockade of TRPA1 inhibited the enhancement of IL-13 and IL-6 induced by DINP.
(A) Immunohistochemistry for IL-13. (B) The expression scores of IL-13. The expression scores were calculated by statistical analysis of optical density of Immunohistochemistry. (C) The levels of IL-6. *p < 0.05, **p < 0.01, compared with saline group; &p < 0.05, &&p < 0.01 compared with FITC group. ##p < 0.01, FITC + DINP200 group versus FITC + DINP200 + HC030031 group. (n = 7).
Figure 4
Figure 4. Blockade of TRPA1 inhibited mast cell degranulation aggravated by DINP.
(A) Immunohistochemistry for Tryptase. A1, saline group. A2, DINP200 group. A3, FITC group. A4, FITC + HC030031 group. A5-A7, FITC + DINP2, FITC + DINP20, FITC + DINP200 groups. (B) The expression scores of Tryptase in mast cells. The expression or activation scores were calculated by statistical analysis of optical density of immunohistochemistry. *p < 0.05, **p < 0.01, compared with saline group; &p < 0.05, &&p < 0.01 compared with FITC group. ##p < 0.01, FITC + DINP200 group versus FITC + DINP200 + HC030031 group. (n = 7).
Figure 5
Figure 5
Blocking NF-κB inhibited the expression of TRPA1 (A) The effect of PDTC treatment on the expression of TRPA1 mRNA. (B) Immunohistochemistry for TRPA1. (C) The expression scores of TRPA1. B1, saline group. B2, FITC group. B3, FITC + PDTC group. B4, FITC + DINP200 group. B5, FITC + DINP200 + PDTC group. B6, Negative control. The expression or activation scores were calculated by statistical analysis of optical density of Immunohistochemistry. *p < 0.05, **p < 0.01, compared with saline group; &p < 0.05, &&p < 0.01 compared with FITC group. ##p < 0.01, FITC + DINP200 group versus FITC + DINP200 + PDTCgroup. (n = 7).
Figure 6
Figure 6. The effect of TRPA1 blockade on NF-κB signaling pathway and the expression of TSLP.
(A) Immunohistochemistry for NF-κB p65 (phospho S536) (B) The activation scores of NF-κB p65 (phospho S536) (C) Immunohistochemistry for TSLP. (D) The expression scores of TSLP. A1, C1, saline group. A2, C2, FITC group. A3, C3, FITC + PDTC group. A4, C4, FITC + DINP200 group. A5, C5, FITC + DINP200 + PDTC group. A6, C6, Negative control. The expression or activation scores were calculated by statistical analysis of optical density of immunohistochemistry. *p < 0.05, **p < 0.01, compared with saline group; &p < 0.05, &&p < 0.01 compared with FITC group. ##p < 0.01, FITC + DINP200 group versus FITC + DINP200 + PDTCgroup. (n = 7).
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