Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1

Abstract

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.

Antimony Compounds Associate with Atopic Dermatitis and Influence Models of Itch and Dysbiosis

“…5 TDI alters commensal lipid production through disruption of nitrogen fixation and alters host physiology through activation of the thermo-itch receptor TRPA1. 12 Antimony is an established influencer of nitrogen fixation in plant biology, 28 and thus, our findings of nitrogen fixation disruption are consistent with the prior literature. Furthermore, nitrogenase-mediated nitrogen fixation and activation of TRPA1 demonstrate a shared biology centered around direct alteration of specific cysteine residues.…”

“…Our proposed mechanism for antimony’s impact on AD is similar to that of our previous work on toluene diisocyanate (TDI) . TDI alters commensal lipid production through disruption of nitrogen fixation and alters host physiology through activation of the thermo-itch receptor TRPA1 . Antimony is an established influencer of nitrogen fixation in plant biology, and thus, our findings of nitrogen fixation disruption are consistent with the prior literature.…”

“…We further demonstrated exposure of health-associated commensal bacteria to TDI shifts the microbial metabolism toward an AD-like phenotype by disrupting ceramide-family lipid production and negating the modeled benefit in commensal isolates of Roseomonas mucosa through disrupting nitrogen fixation . Beyond impacts on commensal bacteria, we have additionally shown that TRPA1 is directly activated by TDI − in a targetable manner operating through the balance of catecholamine signaling …”

“…Antimony is a natural element (elemental signal Sb), to which exposure would be expected from both brake dust in high-traffic areas and dust from aerosolized soil. 13 To further assess for a shared mechanism, we demonstrate that antimony, like TDI, 5,12 inhibited ceramide-family lipid production in R. mucosa and activated TRPA1. While further epidemiologic research will be needed to directly evaluate antimony exposure with surrounding AD prevalence and severity, these data suggest that compounds which are epidemiologically associated with AD, inhibit commensal lipid production, and activate TRPA1 may be causally related to AD pathogenesis.…”

“…5 Beyond impacts on commensal bacteria, we have additionally shown that TRPA1 is directly activated by TDI 6−11 in a targetable manner operating through the balance of catecholamine signaling. 12 While it is possible that products containing TDI brought into the home, wildfires, and car exhaust could generate (di)isocyanate exposure in areas without diisocyanate-produc-ing factories, not every area in the U.S. has high levels of (di)isocyanate pollution. 5 In this report, we aimed to reanalyze regions of the U.S. with low levels of diisocyanate pollution to assess if a different chemical class may contribute.…”