TRPA1 REGULATES CYTOKINE STORM SIGNALING AND CHEMOKINE EXPRESSION IN RESPONSE TO

Halonen L, Luostarinen S, Pemmari A, Moilanen E,

The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Wellbeing Services County of Pirkanmaa, Tampere, Finland

Transient Receptor potential ankyrin 1 (TRPA1) is a cation channel mainly studies in sensory neurons, where it is associated with pain and neurogenic inflammation. We and others have recently shown that TRPA1 is also present in epithelial cells, and its expression and function are regulated by the cytokine environment. This study aims to address the role of TRPA1 in lung inflammation associated with viral infections. Human A459 lung epithelial cell line exposed to cytokines tumor necrosis factor (TNF), interleukin-1β (IL-1β) and interferon-β (IFN-β) was used to model pulmonary antiviral inflammatory response and the effects of TRPA1 antagonists were studied. Gene expression profiles were measured with next generation sequencing (NGS) based RNA-seq, and confirmatory methods. Cytokine treatment significantly enhanced TRPA1 expression and function and caused a major shift in the gene expression profile as seen in the RNA-seq. TRPA1 antagonists changed the expression of 983 protein coding genes in lung epithelial cells exposed to antiviral-type inflammation. Ingenuity Pathway Analysis (IPA) showed an inhibition of nine canonical pathways including “Pathogen Induced Cytokine Storm Signaling”. In this pathway, 13 genes were significantly upregulated by the cytokine treatment, and subsequently downregulated by two different TRPA1 antagonists. Several chemokines were included in the TRPA1 regulated genes. STRING interaction network analysis suggests that TRPA1 regulates chemokine expression through FOS gene and AP-1 transcription factor. These results suggest that TRPA1 antagonists may have beneficial effects in hyperinflammatory lung reactions associated with viral infections.