Epidermal denervation and its effects on keratinocytes and Langerhans cells

Abstract

SummarySkin innervation has been considered to subserve sensory perception only, but several lines of evidence suggest that there are 'effector' influences of skin innervation on the immune system and keratotinocytes. In this study, we transected the sciatic nerves of rats and examined the effects of denervation on the epidermis. In normal skin, the epidermis was densely innervated by fine axons that were immunostained with several axonal markers, including neuronal ubiquitin carboxyl terminal hydrolase (protein gene product 9.5). All of the epidermal axons in the regions innervated by sciatic nerve disappeared within 24-48 h after transection of sciatic nerve, and remained absent as long as subsequent reinnervation by regenerating axonal sprouts was prevented. Denervation produced changes in both the keratinocytes and the Langerhans cells, the bone marrowderived antigen-presenting cells of the epidermis. The thickness of epidermis decreased within 7 days. By 48h after transection, the Langerhans cells and their dendritic processes became intensely immunoreactive for protein gene product. Protein gene product 9.5 expression on Langerhans cells remained prominent as long as skin was denervated, but disappeared with reinnervation. By reverse transcription-polymerase chain reaction, we demonstrated the presence of the transcripts for protein gene product 9.5 in epidermis, consistent with the synthesis of the protein by the Langerhans cells. We conclude that epidermal sensory fibres have novel influences on both keratinocytes and Langerhans cells of the epidermis.

Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells

“…We have confirmed earlier reports of increased PGP9.5 in LCs in rats after sciatic nerve transection (Hsieh et al, 1996;Stankovic et al, 1999) and in the CCI model (Lindenlaub and Sommer, 2002;Lin et al, 2001). …”

“…As reported by others (Hsieh et al, 1996;Stankovic et al, 1999;Lin et al, 2001;Lindenlaub and Sommer, 2002), only low levels of PGP9.5 were detectable in LCs in the skin of normal rats when using antibody dilutions optimized for the demonstration of IENFs (Figs. 1A, B).…”

“…As described previously in both human and rat skin (e.g., Hsieh et al, 1996;McCarthy et al, 1995;Oaklander and Brown, 2004), IENFs emerged from cutaneous nerves and traveled vertically into the epidermis where they branched into terminal arbors consisting of multiple fine branches bearing terminal and en passant boutons (Fig. 1A).…”

“…The paclitaxel-, vincristine-, and ddC-treated animals were sacrificed at the approximate time of peak pain severity in each model: paclitaxel (day 31 (D31) after the first injection; ; vincristine (D16; Siau and Bennett, 2006); and ddC (D8; Joseph et al, 2004). Rats with complete sciatic nerve transection were sacrificed on D2 postsurgery, a time at which degeneration of the IENF is known to be nearly complete (Hsieh et al, 1996). For comparison to the complete nerve transection, the CCI rats were also sacrificed on D2; the CCI pain syndrome is present at this time (Bennett and Xie, 1988).…”

“…Complete and partial transection of a peripheral nerve is known to increase PGP9.5 in epidermal Langerhans cells (LCs; Hsieh et al, 1996;Lin et al, 2001;Lindenlaub and Sommer, 2002). To determine whether paclitaxel, vincristine, and ddC have a similar effect, we counted PGP9.5-positive LCs and confirmed their identity using double labeling with an antibody (OX-6) that is specific for cells of the monocyte lineage.…”