TRPA1 antagonists (Ario Pharma)

Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known for its chemosensory function in neurons, causing pain and neurogenic inflammation. TRPA1 is activated by many noxious compounds including some inflammatory mediators. We and others have shown that TRPA1 is also expressed in epithelial cells, but its function in the epithelial barrier remains unclear. Here, we discovered in RNA-seq studies that inhibition of TRPA1 reduced the expression of a large number of antiviral and inflammatory genes under the influence of the key antiviral cytokine interferon beta in human A549 lung epithelial cells. In the gene ontology analysis, the terms most strongly affected by TRPA1 antagonists included many associated with antiviral defense such as "defense response to virus" and "antiviral innate immune response." To validate the RNA-seq results, selected antiviral genes such as myxovirus resistance protein 1 were further studied and found to be upregulated by TRPA1 by using reverse transcription quantitative polymerase chain reaction and western blotting, pharmacological TRPA1 inhibitors, TRPA1-targeting small interfering RNA, and ex vivo lung tissue cultures from TRPA1-deficient mice. Mechanistically, TRPA1 inhibitors partially reduced interferon beta-induced Ca²⁺ influx, phosphorylation of the transcription factor signal transducer and activator 1, and the interferon-sensitive response element-dependent transcription. These data suggest that TRPA1 mediates cellular signaling and biologically relevant changes in gene expression induced by type I interferons. The results offer TRPA1 as a novel treatment target for inflammatory conditions characterized by enhanced type I interferon activity such as hyperinflammatory states associated with viral infections and some autoimmune diseases, but TRPA1 inhibition may also influence interferon-induced antiviral immunity. SIGNIFICANCE STATEMENT: We found that the transient receptor potential ankyrin 1 channel can promote gene expression changes induced by type I interferons in human lung epithelial cells. Inhibiting transient receptor potential ankyrin 1 could decrease interferon-induced inflammation but could also influence the antiviral state.