Chronic pruritus significantly impacts quality of life and is a unifying symptom in patients with the inflammatory skin diseases bullous pemphigoid (BP) and atopic dermatitis (AD). Limited data are available related to neurophysiologic mechanisms underlying both pruritic conditions. Five patients with BP (n¼2) or AD (n¼3) were followed over a 6-month period while receiving treatment. Disease severity was calculated with the BP Disease Area Index for BP patients or the Eczema Area and Severity Index (EASI) and SCORing Atopic Dermatitis (SCORAD) for AD patients. Itch intensity was measured using the ItchyQuant self-reported pruritus severity scale. Alterations in intraepidermal nerve fiber density (IENFD) were compared between BP patients, AD patients, and healthy controls (HC) (n¼7). Severity scores for patients at baseline ranged from: 11-24 (BPDAI), 0-7.4 (EASI) and 14.91-62.16 (SCORAD). Itch intensity was not altered between baseline and 6-month follow-up (mean 5.2 at both time points). Both AD and BP demonstrated a decreased IENFD compared with HC (AD 4.04 fibers/mm, BP 6.95 fibers/mm, HC 9.34 fibers/mm) at baseline. While there was no significant difference between IENFD in AD and BP at baseline, there was a significant increase in IENFD in both conditions noted at 6-month follow-up, respectively (AD 4.0 fibers/mm, BP 6.9 fibers/mm vs AD 7.4 fibers/mm, BP 11.9 fibers/mm, p¼0.002). These findings suggest that neuroanatomical alterations of epidermal nerve fibers seen in chronic pruritus may be a common phenomenon in seemingly divergent inflammatory skin diseases and reversible with appropriate treatment. Future studies to elucidate mechanistic details related to changes in IENFD may inform potential novel therapeutics.
Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration. Local activation of TRPA1 induces tissue regeneration on distant untreated areas of injury, demonstrating a systemic effect. Activated TRPA1 stimulates local production of interleukin-23 (IL-23) by dermal dendritic cells, leading to activation of circulating dermal IL-17eproducing gd T cells. Genetic ablation of TRPA1, IL-23, dermal dendritic cells, or gd T cells prevents TRPA1-mediated tissue regeneration. These results reveal a cutaneous neuroimmune-regeneration cascade triggered by topical TRPA1 activators that promotes adult mammalian tissue regeneration, presenting a new avenue for research and development of therapies for wounds and scars.
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