Topical application of the anti-microbial chemical triclosan induces immunomodulatory responses through the S100A8/A9-TLR4 pathway

Nikki B Marshall,Ewa Lukomska,Ajay P Nayak,Carrie M Long,Justin M Hettick,Stacey E Anderson

doi:10.1080/1547691x.2016.1258094

Abstract

The anti-microbial compound triclosan is incorporated into numerous consumer products and is detectable in the urine of 75% of the general United States population. Recent epidemiological studies report positive associations with urinary triclosan levels and allergic disease. Although not sensitizing, earlier studies previously found that repeated topical application of triclosan augments the allergic response to ovalbumin (OVA) though a thymic stromal lymphopoietin (TSLP) pathway in mice. In the present study, early immunological effects following triclosan exposure were further evaluated following topical application in a murine model. These investigations revealed abundant expression of S100A8/A9, which reportedly acts as an endogenous ligand for Toll-like Receptor 4 (TLR4), in skin tissues and in infiltrating leukocytes during topical application of 0.75–3.0% triclosan. Expression of Tlr4 along with Tlr1, Tlr2 and Tlr6 increased in skin tissues over time with triclosan exposure; high levels of TLR4 were expressed on skin-infiltrating leukocytes. In vivo antibody blockade of the TLR4/MD-2 receptor complex impaired local inflammatory responses after four days, as evidenced by decreased Il6, Tnfα, S100a8, S100a9, Tlr1, Tlr2, Tlr4 and Tlr6 expression in the skin and decreased lymph node cellularity and production of IL-4 and IL-13 by lymph node T-cells. After nine days of triclosan exposure with TLR4/MD-2 blockade, impaired T-helper cell type 2 (TH2) cytokine responses were sustained, but other early effects on skin and lymph node cellularity were lost; this suggested alternative ligands/receptors compensated for the loss of TLR4 signaling. Taken together, these data suggest the S100A8/A9-TLR4 pathway plays an early role in augmenting immunomodulatory responses with triclosan exposure and support a role for the innate immune system in chemical adjuvancy.

Highlights

Triclosan is a low molecular weight anti-microbial found in numerous consumer products such as hand soaps, lotions, and toothpaste, and is incorporated into items such as kitchen utensils, clothing, furniture, and medical devices
Our laboratory has found that topical skin application of triclosan augments allergic responses in a mouse ovalbumin (OVA) asthma model and it does not act as an allergic sensitizer (Anderson et al 2012, 2015), it can induce expression of the cytokine thymic stromal lymphopoietin (TSLP) in the skin tissue that augments IL-4þ IL-13þ T-helper cell type 2 (TH2) immune responses (Marshall et al 2015)
Because the Toll-like Receptor 4 (TLR4) pathway has been shown to play a role in allergic inflammation (Miller & Modlin 2007), the current study focused on identifying a potential role for the TLR4 pathway in augmenting immunomodulatory responses following triclosan exposure

Summary

Introduction

Triclosan is a low molecular weight anti-microbial found in numerous consumer products such as hand soaps, lotions, and toothpaste, and is incorporated into items such as kitchen utensils, clothing, furniture, and medical devices. It is so ubiquitous, 75% of the general United States population have detectable levels in their urine (Calafat et al 2008). With increasing reports that exposure to anti-microbial chemicals has the potential to induce or augment allergic disease, further studies are needed to help identify the mechanisms by which this occurs to help understand ways to prevent or circumvent these effects

Methods

Results

Conclusion