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

Quanzhi Hou; Travis Barr; Lucy Gee; Jeff Vickers; James Wymer; Elisa Borsani; Luigi Rodella; Spiro Getsios; Trisha Burdo; Elan Eisenberg; Udayan Guha; Robert Lavker; John Kessler; Sridar Chittur; Dennis Fiorino; Frank Rice; Phillip Albrecht

doi:10.1016/j.pain.2011.04.033

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

Quanzhi Hou, Travis Barr, Lucy Gee, Jeff Vickers, James Wymer, Elisa Borsani, Luigi Rodella, Spiro Getsios, Trisha Burdo, Elan Eisenberg, Udayan Guha, Robert Lavker, John Kessler, Sridar Chittur, Dennis Fiorino, Frank Rice, Phillip Albrecht^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

127 Scopus citations

Abstract

Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebrospinal fluid (CSF) 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, quantitative Polymerase Chain Reaction (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, Calcitonin receptor-like receptor (CRLR), Receptor activity-modifying protein 1 (RAMP1), CGRP-receptor component protein (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.

Original language	English (US)
Pages (from-to)	2036-2051
Number of pages	16
Journal	Pain
Volume	152
Issue number	9
DOIs	https://doi.org/10.1016/j.pain.2011.04.033
State	Published - Sep 2011

Funding

The authors thank Dr. I. Silos-Santiago for facilitating the PHN and diabetic neuropathy portions of this research; Dr. L.B. Hough, Albany Medical College, for assistance in producing the SNL rats; Dr. K. Ren, University of Maryland, for providing CFA-injected rat tissues; Dr. K.C. Williams, Boston College, for providing SIV monkey tissues; Dr. A. Miller for obtaining rhesus palmar skin from SIV-infected macaques; Dr. B. Herron, Wadsworth Center, for providing primary mouse cell cultures; Dr. M. DiPersio, Albany Medical College, for providing MK116 cells; Dr. S. Temple, New York State Neural Stem Cell Institute, for providing primary mouse fibroblasts; Dr. R. Ferland and Dr. L. Jacobsen, Albany Medical College, for providing trigeminal ganglia tissue; Dr. R. Keller, Albany Medical College, for expert assistance with qPCR experiments; Dr. Y. Huang, Albany Medical College, for assistance with Western blotting experiments; Mrs. Marilyn Dockum, Albany Medical College, for assistance in processing tissues; and Ms. Jennifer Jewitt, Northwestern University, for assistance with transgenic mice tissue. We also thank the Northwestern University Skin Disease Research Center Keratinocyte Core Facility (NIH/NIAMS–1P30AR057216-01). Portions of this research study were supported by an AMC training grant (NIDA DA07307). The authors declare that there are no real or percieved conflicts of interest associated with the research data presented.

Keywords

BMP-4
Cutaneous innervation
Dermatology
Noggin
Sensory transduction
Skin

ASJC Scopus subject areas

Clinical Neurology
Neurology
Anesthesiology and Pain Medicine

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10.1016/j.pain.2011.04.033

Cite this

Hou, Q., Barr, T., Gee, L., Vickers, J., Wymer, J., Borsani, E., Rodella, L., Getsios, S., Burdo, T., Eisenberg, E., Guha, U., Lavker, R., Kessler, J., Chittur, S., Fiorino, D., Rice, F., & Albrecht, P. (2011). Keratinocyte expression of calcitonin gene-related peptide β: Implications for neuropathic and inflammatory pain mechanisms. Pain, 152(9), 2036-2051. https://doi.org/10.1016/j.pain.2011.04.033

@article{8031776eaf0742feb3fc38312cb7532d,

title = "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 cerebrospinal fluid (CSF) 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, quantitative Polymerase Chain Reaction (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, Calcitonin receptor-like receptor (CRLR), Receptor activity-modifying protein 1 (RAMP1), CGRP-receptor component protein (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.",

keywords = "BMP-4, Cutaneous innervation, Dermatology, Noggin, Sensory transduction, Skin",

author = "Quanzhi Hou and Travis Barr and Lucy Gee and Jeff Vickers and James Wymer and Elisa Borsani and Luigi Rodella and Spiro Getsios and Trisha Burdo and Elan Eisenberg and Udayan Guha and Robert Lavker and John Kessler and Sridar Chittur and Dennis Fiorino and Frank Rice and Phillip Albrecht",

note = "Funding Information: The authors thank Dr. I. Silos-Santiago for facilitating the PHN and diabetic neuropathy portions of this research; Dr. L.B. Hough, Albany Medical College, for assistance in producing the SNL rats; Dr. K. Ren, University of Maryland, for providing CFA-injected rat tissues; Dr. K.C. Williams, Boston College, for providing SIV monkey tissues; Dr. A. Miller for obtaining rhesus palmar skin from SIV-infected macaques; Dr. B. Herron, Wadsworth Center, for providing primary mouse cell cultures; Dr. M. DiPersio, Albany Medical College, for providing MK116 cells; Dr. S. Temple, New York State Neural Stem Cell Institute, for providing primary mouse fibroblasts; Dr. R. Ferland and Dr. L. Jacobsen, Albany Medical College, for providing trigeminal ganglia tissue; Dr. R. Keller, Albany Medical College, for expert assistance with qPCR experiments; Dr. Y. Huang, Albany Medical College, for assistance with Western blotting experiments; Mrs. Marilyn Dockum, Albany Medical College, for assistance in processing tissues; and Ms. Jennifer Jewitt, Northwestern University, for assistance with transgenic mice tissue. We also thank the Northwestern University Skin Disease Research Center Keratinocyte Core Facility (NIH/NIAMS–1P30AR057216-01). Portions of this research study were supported by an AMC training grant (NIDA DA07307). The authors declare that there are no real or percieved conflicts of interest associated with the research data presented. ",

year = "2011",

month = sep,

doi = "10.1016/j.pain.2011.04.033",

language = "English (US)",

volume = "152",

pages = "2036--2051",

journal = "Pain",

issn = "0304-3959",

publisher = "Lippincott Williams and Wilkins",

number = "9",

}

Hou, Q, Barr, T, Gee, L, Vickers, J, Wymer, J, Borsani, E, Rodella, L, Getsios, S, Burdo, T, Eisenberg, E, Guha, U, Lavker, R , Kessler, J, Chittur, S, Fiorino, D, Rice, F & Albrecht, P 2011, 'Keratinocyte expression of calcitonin gene-related peptide β: Implications for neuropathic and inflammatory pain mechanisms', Pain, vol. 152, no. 9, pp. 2036-2051. https://doi.org/10.1016/j.pain.2011.04.033

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T1 - Keratinocyte expression of calcitonin gene-related peptide β

T2 - Implications for neuropathic and inflammatory pain mechanisms

AU - Hou, Quanzhi

AU - Barr, Travis

AU - Gee, Lucy

AU - Vickers, Jeff

AU - Wymer, James

AU - Borsani, Elisa

AU - Rodella, Luigi

AU - Getsios, Spiro

AU - Burdo, Trisha

AU - Eisenberg, Elan

AU - Guha, Udayan

AU - Lavker, Robert

AU - Kessler, John

AU - Chittur, Sridar

AU - Fiorino, Dennis

AU - Rice, Frank

AU - Albrecht, Phillip

N1 - Funding Information: The authors thank Dr. I. Silos-Santiago for facilitating the PHN and diabetic neuropathy portions of this research; Dr. L.B. Hough, Albany Medical College, for assistance in producing the SNL rats; Dr. K. Ren, University of Maryland, for providing CFA-injected rat tissues; Dr. K.C. Williams, Boston College, for providing SIV monkey tissues; Dr. A. Miller for obtaining rhesus palmar skin from SIV-infected macaques; Dr. B. Herron, Wadsworth Center, for providing primary mouse cell cultures; Dr. M. DiPersio, Albany Medical College, for providing MK116 cells; Dr. S. Temple, New York State Neural Stem Cell Institute, for providing primary mouse fibroblasts; Dr. R. Ferland and Dr. L. Jacobsen, Albany Medical College, for providing trigeminal ganglia tissue; Dr. R. Keller, Albany Medical College, for expert assistance with qPCR experiments; Dr. Y. Huang, Albany Medical College, for assistance with Western blotting experiments; Mrs. Marilyn Dockum, Albany Medical College, for assistance in processing tissues; and Ms. Jennifer Jewitt, Northwestern University, for assistance with transgenic mice tissue. We also thank the Northwestern University Skin Disease Research Center Keratinocyte Core Facility (NIH/NIAMS–1P30AR057216-01). Portions of this research study were supported by an AMC training grant (NIDA DA07307). The authors declare that there are no real or percieved conflicts of interest associated with the research data presented.

PY - 2011/9

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N2 - Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebrospinal fluid (CSF) 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, quantitative Polymerase Chain Reaction (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, Calcitonin receptor-like receptor (CRLR), Receptor activity-modifying protein 1 (RAMP1), CGRP-receptor component protein (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.

AB - Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebrospinal fluid (CSF) 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, quantitative Polymerase Chain Reaction (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, Calcitonin receptor-like receptor (CRLR), Receptor activity-modifying protein 1 (RAMP1), CGRP-receptor component protein (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.

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KW - Dermatology

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KW - Sensory transduction

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

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