TRPA1 in Skin and Lung Inflammation

Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel has emerged during the past two decades not only as a sensory neuronal nociceptive channel, but also as a mediator of neurogenic inflammation. Non-neuronal TRPA1 expression has also been reported. The aim of the present study was to investigate TRPA1 expression in epithelial cells of the skin and lungs under inflammatory conditions, and to characterize the consequences of TRPA1 activation on their inflammatory response.

We found that TRPA1 was expressed in human HaCaT keratinocytes and in human A549 lung epithelial cells. The central inflammatory cytokine tumor necrosis factor alpha (TNF-α) significantly enhanced the expression of functional TRPA1 in human keratinocytes. Similarly in lung epithelial cells, TNF-α and interleukin 1 beta (IL-1β) upregulated TRPA1 expression. The T helper 1 (Th1) and T helper 2 (Th2)-related cytokines interferon gamma (IFN-γ) and interleukins 4 and 13 (IL-4 and IL-13), respectively, were found to have opposite effects on TRPA1 expression. Th1-type inflammation enhanced, and Th2-type inflammation decreased TRPA1 expression.

The effects of inflammation-related signaling pathways and selected anti-inflammatory drugs on TRPA1 expression were also studied. TNF-α-induced TRPA1 expression was mediated through NF-κB and the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways. The Janus kinase (JAK) inhibitors baricitinib and tofacitinib reversed the effects of IFN-γ and IL-4 on TRPA1 expression. The calcineurin inhibitors cyclosporine and tacrolimus downregulated TNF-α-induced TRPA1 expression. While the glucocorticoid dexamethasone had a wide-spectrum suppressive effect on TRPA1 expression independent of the type of inflammation.

TRPA1 was found to mediate the cytokine-induced production of inflammatory factors by epithelial cells, particularly chemokines, including monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8), chemokine (C-X-C motif) ligand 6 (CXCL6) and lipocalin-2 (LCN2).

As an important finding, TRPA1 was discovered to be activated by and to mediate the effects of type I interferons in human lung epithelial cells. In a transcriptome- wide analysis, TRPA1 enhanced the expression of a wide range of antiviral genes but also inflammatory genes induced by interferon beta (IFN-β). These included key antiviral genes such as MX dynamin like GTPase 1 (MX1) and the pattern recognition receptor DEXD/H-box helicase 58 (DDX58, also known as RIG-I).

The contact sensitizer methylisothiazolinone (MIT) was characterized as a novel TRPA1 agonist and TRPA1 was found to be involved in mediating MIT-induced inflammatory edema and allergic contact dermatitis in in vivo models.

In conclusion, the present findings support a model where the type of inflammation determines the level of TRPA1 expression and function, which is a new concept. The results show that TRPA1 is involved in mediating the effects of key proinflammatory cytokines in epithelial cells to promote inflammation; and to enhance the expression of antiviral genes, which has not been previously described. The results underline the significance of TRPA1 as an effector and regulator of the first-line defense of skin and lung epithelial barrier. In addition, the results offer TRPA1 as a potential drug target to treat inflammatory conditions in the skin and lungs. The studies build a foundation for novel translational studies but also lead to new lines of inquiry especially on the role of TRPA1 in antiviral immunity, which should be better understood when targeting this channel for pharmacotherapy.