New mechanisms in diisocyanate-mediated allergy/toxicity: are microRNAs in play?

Abstract

Purpose of review: To describe recent findings of diisocyanate-mediated mechanisms in allergy and toxicology by addressing the role of microRNA (miR) in immune responses that may contribute to the development of occupational asthma (OA).

Recent findings: Studies of diisocyanate asthma have traditionally focused on the immune and inflammatory patterns associated with diisocyanate exposures; however, recognized knowledge gaps exist regarding the detailed molecular mechanism(s) of pathogenesis. Recent studies demonstrate the critical role endogenous microRNAs play as gene regulators in maintaining homeostasis of the human body, and in the pathophysiology of many diseases including asthma. Given that diisocyanate-OA shares many pathophysiological characteristics with asthma, it is likely that miR-mediated mechanisms are involved in the pathophysiology of diisocyanate-OA. Recent reports have shown that changes in expression of endogenous miRs are associated with exposure to the occupationally relevant diisocyanates, toluene diisocyanate (TDI) and methylene diphenyl diisocyanate (MDI). Continued mechanistic study of these relevant miRs may lead to the development of novel biomarkers of occupational exposure and/or provide efficacious targets for therapeutic strategies in diisocyanate asthma.

Summary: The molecular mechanisms underlying diisocyanate-OA pathophysiology are heterogeneous and complicated. In this review, we highlight recent research into the roles and potential regulation of miRs in diisocyanate-OA.

FIGURE 1.

Chemical structure of (a) toluene diisocyanate (TDI) including 2,4-TDI, and 2,6-TDI and (b) 4,4’-methylene diphenyl diisocyanate (MDI).

FIGURE 2.

Schematic of microRNA biosynthesis, processing, and maturation as well as potential downstream targets regulated by diisocyanate-associated miRs (see Table 1, Supplemental Digital Content, http://links.lww.com/COAI/A40.) after exposure to TDI [25] or MDI [^▪,^▪–^▪]. Following cellular exposure to TDI/MDI, exposure-mediated activation/inhibition of signal transduction pathways recruits transcriptional factors (TFs) to promote/inhibit the expression of primary-miR transcripts. Activators/suppressors of miR maturation and noncoding RNA species (lncRNAs and circRNA) of miR degradation may be recruited after TDI/MDI exposure to regulate expression of mature miRs in the cytosol. TDI/MDI exposure-mediated miRs thus target and regulate multiple mRNA transcripts encoding proteins that may play important roles in immune response, transcriptional regulation or other pathways leading to OA. Note. Some illustrated schematics were obtained from motifolio templates (www.motifolio.com, Accessed July 8, 2024).

FIGURE 3.

Potential miR-mediated marker and chemokine expression following MDI/MDI-GSH exposure in macrophages. Note. Some illustrated schematics were obtained from motifolio templates (www.motifolio.com., Accessed July 8, 2024).