Keratinocyte expression of calcitonin gene-related peptide β: Implications for neuropathic and inflammatory pain mechanisms

Abstract

Calcitonin Gene-Related Peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebral spinal fluid under a variety of inflammatory and chronic pain conditions, presumably derived from peptidergic C and Aδ innervation. Herein, CGRP immunolabeling (IL) was detected in epidermal keratinocytes at levels that were especially high and widespread in the skin of humans from locations afflicted with postherpetic neuralgia (PHN) and complex region pain syndrome type 1 (CRPS), of monkeys infected with simian immunodeficiency virus, and of rats subjected to L5/L6 spinal nerve ligation, sciatic nerve chronic constriction, and subcutaneous injection of Complete Freund’s Adjuvant. Increased CGRP-IL was also detected in epidermal keratinocytes of transgenic mice with keratin-14 promoter driven overexpression of noggin, an antagonist to BMP-4 signaling. Transcriptome microarray, qPCR, and Western blot analyses using laser captured mouse epidermis from transgenics, monolayer cultures of human and mouse keratinocytes, and multilayer human keratinocyte organotypic cultures, revealed that keratinocytes express predominantly the beta isoform of CGRP. Cutaneous peptidergic innervation has been shown to express predominantly the alpha isoform of CGRP. Keratinocytes also express the cognate CGRP receptor components, CRLR, RAMP1, and RCP, consistent with known observations that CGRP promotes several functional changes in keratinocytes, including proliferation and cytokine production. Our results indicate that keratinocyte derived CGRPβ may modulate epidermal homeostasis through autocrine/paracrine signaling and may contribute to chronic pain under pathological conditions.

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

“…It is possible that NADA treatment reduced CGRP secretion via the acute desensitization of TRPV1, but this seems unlikely because, similar to other reports, we observed that NADA TRPV1-dependently increases levels of substance P in the circulation. Finally, the neuropeptides in the plasma may have been derived from nonneuronal cells, such as keratinocytes, which have been shown to express CGRPb, or subsets of leukocytes that express substance P (69,72).…”

Clinical, Histologic, and Molecular Analysis of Differences Between Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

“…24 Both CGRP isoforms, -α and -β, have similar activity, though CGRP-α is the predominant isoform in human skin and colocalizes with substance P. 24 Recent evidence suggests that CGRP-β is produced by epidermal keratinocytes and upregulated in certain cutaneous pain syndromes. 25 Upregulation of substance P and CGRP may be mediated through activation of nonselective cation channels TRPV1 and TRPA1 (transient receptor potentials vanilloid 1 and ankyrin 1); agonists of TRPV1 and TRPA1 have been shown in mice to cause increased blood flow via upregulation of vasodilator neuropeptides such as substance P and CGRP. 26 Certain stimuli (eg, heat, cold, spices) may lead to activation of TRPV1 and TRPA1, with subsequent upregulation of substance P and CGRP and further downstream vasodilation, producing the typical flush of rosacea.…”

Transforming Growth Factor-β in Normal Nociceptive Processing and Pathological Pain Models

“…CGRP conveys pain information from nociceptors to second-order neurons in the spinal cord, and it is also an important mediator of normal inflammatory pain response to injuries [60,61]. CGRP is also involved in the development of hyperalgesia in inflammation-or nerveinjury-induced chronic pain [62]. Studies in vivo suggest that the conditional overexpression of BMP4 in mouse skin keratinocytes reduces the number of non-peptidergic neurons in sensory ganglia and the density of target innervation, but the nerve endings from CGRP peptidergic neurons were markedly increased [63].This phenotype is consistent with the aforementioned effect of BMP signaling on CGRP expression in vitro [45].…”