INTRODUCTION
The transient receptor potential (TRP) channel superfamily consists of several variably selective cation channels expressed throughout the human body.1 These channels are activated through various mechanisms and primarily function as sensory receptors, mediating pain sensations, temperature, vision, pressure, osmolality, olfaction, and more.2 The six members of the vanilloid subfamily of TRP channels (TRPV1-6) are named for the vanilloid compound capsaicin originally found to activate the first TRPV channel (vanilloid receptor 1/TRPV1). However, they are now known to be activated by many exogenous and endogenous ligands. TRPV1, TRPV3, and TRPV4 are expressed in several tissues including the skin, leading to myriad cutaneous functions.3 Dermatologists benefit from understanding how TRPVs contribute to the neurogenic inflammation that underlies many dermatologic diseases and emerging therapeutics that leverage this connection.
Transient Receptor Potential Vanilloid subfamily
The skin is a major somatosensory organ. Afferent nerve endings throughout the epidermis and dermis detect various stimuli, transducing this information into electrical activity that the central nervous system (CNS) may interpret and respond to. TRPV in the skin are found on sensory nerve fibers as well as keratinocytes, mast cells, dendritic cells, sebaceous cells, dermal endothelial cells, hair follicles, and eccrine glands.4 Tissue expression and cutaneous functions of TRPV1-4 are summarized in the Table.
Neurogenic Inflammation
Cutaneous neurogenic inflammation is created through the bidirectional interaction of keratinocytes and skin-residing immune cells with nerve endings and their secreted neuropeptide mediators.5 TRPV1 and TRP ankyrin 1 (TRPA1) appear to be predominant TRP channels involved in neurogenic inflammation.5 Activation of TRPV1 and TRPA1 located on sensory neurons leads to increased intracellular calcium and the subsequent release of the neuropeptides, namely substance P (SP) and calcitonin gene-related peptide (CGRP); these neuropeptides, in turn, promote mast cell degranulation, vasodilation, and infiltration of neutrophils and T lymphocytes.6 Moreover, the release of neuropeptides following activation of TRPV1 and TRPA1 modulate proinflammatory gene expression and induce keratinocytes to produce interleukin (IL)-1-alpha, IL-6, and IL-8.6 TRPV1 is a central integrator of sensation induced by pruritogenic stimuli;7 however, although not part of the vanilloid subfamily, it has been suggested that TRPA1 is required for itch transduction and skin barrier defects found in chronic pruritus.8 Notably, TRPV1 channels may become hypersensitive in the setting of proinflammatory or proalgesic mediators such as extracellular protons, neurotrophins, or bradykinin, thus mediating hyperalgesia.9,10
Neurogenic inflammation underlies many inflammatory skin diseases, including rosacea, atopic dermatitis (AD), and sensitive skin.
