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Abstract Background Atopic dermatitis (AD) is a chronic, inflammatory disease characterized by dry, pruritic skin. In the U.S., the prevalence of AD has increased over three-fold since the 1970s. We previously reported a geographic association between isocyanate-containing air pollution and AD as well as mechanistic data demonstrating that isocyanates induce skin dysbiosis and activate the host itch receptor TRPA1. However, non-spatial models are susceptible to spatial confounding and may overlook other meaningful associations. Methods We added spatial analysis to our prior model, contrasting pollution data with clinical visits. In addition, we conducted a retrospective case-control survey of childhood exposure to BTEX-related products. Finally, we assessed implicated compounds, in pure form and as part of synthetic fabric, for their effect on the growth and metabolism of skin commensal bacteria. Results Spatial analysis implicate benzene, toluene, ethylbenzene, and, most significantly, xylene (BTEX) compounds. Survey odds ratios for AD were significant for xylene-derived polyester bed sheets (OR = 9.5; CI 2.2–40.1) and diisocyanate-containing wallpaper adhesive (OR = 6.5; CI 1.5–27.8). Staphylococcus aureus lives longer on synthetic textiles compared to natural textiles. Meanwhile, synthetic fabric exposure shifts the lipid metabolism of health-associated commensals (Roseomonas mucosa and S. epidermidis) away from therapeutic pathways. Conclusions We propose that BTEX chemicals in their raw forms and in synthetic products represent a unifying hypothesis for environmentally induced AD flares through their ability to create dysbiosis in the skin microbiota and directly activate TRPA1. Unequal distribution of these pollutants may also influence racial disparities in AD rates.

Background: Better understanding of the interaction between metabolism and immune response will be key to understanding physiology and disease. Tumor Necrosis Factor-alpha (TNFα) has been studied widely. However, despite the extensive knowledge about TNFα, the cytokine appears to induce not only variable, but often contradictory, effects on inflammation and cell proliferation. Despite advancements in the metabolomics field, it is still difficult to analyze the types of multi-dose, multi-time point studies needed for elucidating the varied immunologic responses induced by TNFα. Results: We studied the dose and time course effects of TNFα on murine fibroblast cultures and further elucidated these connections using selective blockade of the TNF receptors (TNFR1 and TNFR2). To streamline analysis, we developed a method to collate the metabolic pathway output from MetaboAnalyst into a single value for the Index of pathway significance (IPS). Using this metric, we tested dose-, time-, and receptor-dependent effects of TNFα signaling on cell metabolism. Guided by these results, we then demonstrate that alanine supplementation enriched TNFR1-related responses in both cell and mouse models. Conclusions: Our results suggest that TNFα, particularly when signaling through TNFR1, may preferentially use alanine metabolism for energy. These results are limited in by cell type used and immune outputs measured. However, we anticipate that our novel method may assist other researchers in identifying metabolic targets that influence their disease or model of interest through simplifying the analysis of multi-condition experiments. Furthermore, our results endorse the consideration of follow up studies in immunometabolism to improve outcomes in TNF-mediated diseases.

BackgroundDespite the recent expansion of treatment options in atopic dermatitis (AD), most management responsibilities fall on the patient and/or caregivers. Disease control often requires vigilance about and avoidance of common exposures, however the concerns for patients and caregivers living with AD have not been well enumerated.MethodsAn IRB approved survey was distributed to the public to evaluate the patient and caregiver concerns for topical exposures and potential triggers.Results323 people accessed the link to the survey with 259 providing response to at least one section of questions (response rate 80.2%). Results indicated that temperature and other weather related changes were the most common trigger. Nearly all respondents avoided at least one topical ingredient, with fragrances being the most common. Steroid exposure was common, however respondents expressed concerns about overall steroid exposure.ConclusionsOur results attempt to enumerate the daily topical exposure concerns for patients and caregivers living with AD. While our online survey is both limited and without mechanistic insights, our results provide insight to providers by highlighting the role of temperature in AD symptoms; identifying commonly perceived triggers; indicating the value of provider insight for topical product selection; and indicating that no specific aspect of topical corticosteroid exposure may alleviate the general steroid concerns for patients or caregivers.

We recently used EPA databases to identify that isocyanates, most notably toluene diisocyanate (TDI), were the pollutant class with the strongest spatiotemporal and epidemiologic association with atopic dermatitis (AD). Our findings demonstrated that isocyanates like TDI disrupted lipid homeostasis and modeled benefit in commensal bacteria like Roseomonas mucosa through disrupting nitrogen fixation. However, TDI has also been established to activate transient receptor potential ankyrin 1 (TRPA1) in mice and thus could directly contribute to AD through induction of itch, rash, and psychological stress. Using cell culture and mouse models, we now demonstrate that TDI induced skin inflammation in mice as well as calcium influx in human neurons; each of these findings were dependent on TRPA1. Furthermore, TRPA1 blockade synergized with R. mucosa treatment in mice to improve TDI-independent models of AD. Finally, we show that the cellular effects of TRPA1 are related to shifting the balance of the tyrosine metabolites epinephrine and dopamine. This work provides added insight into the potential role, and therapeutic potential, or TRPA1 in the pathogenesis of AD.