TRPV1: Role in Skin and Skin Diseases and Potential Target for Improving Wound Healing

Abstract

Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient receptor potential cation channel, subfamily V member 1 (TRPV1) in wound healing, with the intent of targeting it in treatment of non-healing wounds. TRPV1 structure and function as well as the outcomes of TRPV1-targeted therapies utilized in several diseases and tissues are summarized. In skin, keratinocytes, sebocytes, nociceptors, and several immune cells express TRPV1, making it an attractive focus area for treating wounds. Many intrinsic and extrinsic factors confound the function and targeting of TRPV1 and may lead to adverse or off-target effects. Therefore, a better understanding of what is known about the role of TRPV1 in skin and wound healing will inform future therapies to treat impaired and chronic wounds to improve healing.

Keywords: TRPV1; keratinocytes; nociceptors; pilosebaceous unit; skin; wound healing.

Figure 1

Sensory nerves of the skin and transient receptor potential cation channel, subfamily V member 1 (TRPV1) expression. The skin is innervated by sensory nerves originating from the dorsal root ganglion (not in the skin as noted by the dashed line) that can be categorized as myelinated (Aβ- and Aδ-fibers) or unmyelinated (C-fibers). C-fibers can be further characterized as peptidergic or non-peptidergic and terminate in the epidermis. C-fibers, mast cells, keratinocytes, sebocytes, and hair follicles, to name a few, have been shown to express TRPV1 (green tetramer, not to scale).

Figure 2

Transient receptor potential cation channel, subfamily V member 1 (TRPV1) structure. (a) The TRPV1 channel is a nonspecific ion channel expressed in the cell membrane made of four subunits with 838 amino acids per subunit, and homo- and heterotetrameric forms. When activated by capsaicin (CAP) or other stimuli, the dual gate pore opens and allows ion influx into the cell, with high relative permeability to calcium ions. (b) Each subunit of the TRPV1 channel is made up of six transmembrane domains. The pore loop is located between the S5 and S6 segments. Both the N and C termini are located intracellularly where they interact with CAP and phosphatases. The N terminus contains six ankyrin repeats, known as ankyrin repeat domain of TRPV1 (TRPV1-ARD), as well as a calmodulin (CaM) binding site. The C terminus contains the TRP box and a CaM binding site involved in stability and function. Adapted from [24] Figure 2.

Figure 3

Effects of different activators of TRPV1 on keratinocyte function and signaling. In vitro studies have elucidated TRPV1 is expressed by keratinocytes and activated by several known stimuli. Keratinocyte intra- and extracellular signaling and, in some cases, function was determined post-activation. This figure represents the findings of these various in vitro studies, with different dashed lines showing the downstream signaling/function each activator induced. The signaling shown may or may not occur simultaneously, and this figure demonstrates the overlap in signaling outcomes of the various stimuli. Heat—>43 °C, UV—ultraviolet irradiation, CAP—capsaicin, H⁺—acidic environment.

Figure 4

Impact of capsaicin (CAP) on substructures of the pilosebaceous unit. Keratinocytes and their stem cell precursors express TRPV1 (green tetramer, not to scale) and, when stimulated with CAP, show increased expression of growth inhibition factors and decreased growth promotion factors, accompanied by increased apoptosis. CAP activation inhibits lipid synthesis in the sebaceous gland (SG). Additionally, low dose CAP stimulation in the SG has increased proliferation, but high dose CAP stimulation leads to cell death.

Figure 5

TRPV1 role in different types of wounds. In vivo and ex vivo studies have looked at the outcomes of various types of wounding either in the presence or absence of TRPV1 or with activation or inhibition of TRPV1. These outcomes are summarized in Table 2 and here graphically. Generally, it appears that TRPV1 activation, mainly in keratinocytes, leads to inflammation and delayed healing in tape strip, burn, and UVB wounds. The absence of TRPV1 increases heat hyperalgesia in incision wounds. TRPV1 antagonism or blockade improves healing in tape strip wounds and has an anti-inflammatory effect in burn and UVB wounds.