TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization

Abstract

Cutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.

Keywords: inflammatory gene regulation; neurogenic skin inflammation; pruritus; sensory nerve.

Figure 1

Common intracellular GPCR, RTK and Ca ²⁺ pathways regulate via the activation and sensitization of TRPV1 and TRPA1. The G protein-coupled receptor (GPCR) and receptor tyrosine kinase (RTK) activation stimulate phospholipase C (PLC), which leads to phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and the consequent release of the transient receptor potential (TRP) channels from its inhibitory control, triggering the formation of 1,4,5-trisphosphate (IP3) and diaglycerol (DAG) as well as the influx of Ca²⁺ via TRP vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1). Then, DAG can directly activate both TRP channels, and protein kinase C (PKC) activation by DAG enhances TRP activity, sensitizing both channels. IP3 formation promotes Ca²⁺ release from the endoplasmic reticulum and increases the iCa²⁺ concentration. GPCRs can also activate the phospholipase A2 (PLA2) and adenylate cyclase pathways, which lead to protein kinase A (PKA) stimulation and the formation of arachidonic acid (AA) metabolites and products. PKA acts directly sensitize the TRP channels, while AA metabolites and products directly activate the TRP channels. Both TRPV1 and TRPV1 can directly or indirectly regulate the activity of the other by direct interaction or via the iCa²⁺ concentration, resulting in a cross-sensitization/desensitization process. The elevation of iCa²⁺ triggers the exocytosis of inflammatory mediators and stimulates both Ca²⁺/calmodulin-dependent kinase II (CAMKII) and calcineurin, which sensitize and desensitize TRPV1, respectively. Both kinases are also involved in the regulation of inflammatory genes via nuclear factor of activated T-cell (NFAT) translocation to the nucleus