Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Keisuke Koga, Ryo Yamagata, Keita Kohno, Takuya Yamane, Miho Shiratori-Hayashi, Yuta Kohro, Hidetoshi Tozaki-Saitoh, Makoto Tsuda

Research output: Contribution to journalArticle

Abstract

Background: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. Objective: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. Methods: Patch-clamp recordings from enhanced green fluorescent protein (EGFP)–expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. Results: We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9–mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. Conclusion: Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non–cell-autonomous mechanism involving LCN2 derived from reactive astrocytes.

Original languageEnglish
Pages (from-to)183-191.e10
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number1
DOIs
Publication statusPublished - Jan 2020

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Bombesin Receptors
Gastrin-Releasing Peptide
Neurons
Posterior Horn Cells
Astrocytes
Contact Dermatitis
Clustered Regularly Interspaced Short Palindromic Repeats
Dependovirus
Skin Diseases
Spinal Cord

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor. / Koga, Keisuke; Yamagata, Ryo; Kohno, Keita; Yamane, Takuya; Shiratori-Hayashi, Miho; Kohro, Yuta; Tozaki-Saitoh, Hidetoshi; Tsuda, Makoto.

In: Journal of Allergy and Clinical Immunology, Vol. 145, No. 1, 01.2020, p. 183-191.e10.

Research output: Contribution to journalArticle

Koga, K, Yamagata, R, Kohno, K, Yamane, T, Shiratori-Hayashi, M, Kohro, Y, Tozaki-Saitoh, H & Tsuda, M 2020, 'Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor', Journal of Allergy and Clinical Immunology, vol. 145, no. 1, pp. 183-191.e10. https://doi.org/10.1016/j.jaci.2019.09.034
Koga, Keisuke ; Yamagata, Ryo ; Kohno, Keita ; Yamane, Takuya ; Shiratori-Hayashi, Miho ; Kohro, Yuta ; Tozaki-Saitoh, Hidetoshi ; Tsuda, Makoto. / Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor. In: Journal of Allergy and Clinical Immunology. 2020 ; Vol. 145, No. 1. pp. 183-191.e10.
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abstract = "Background: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. Objective: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. Methods: Patch-clamp recordings from enhanced green fluorescent protein (EGFP)–expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. Results: We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9–mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. Conclusion: Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non–cell-autonomous mechanism involving LCN2 derived from reactive astrocytes.",
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AU - Shiratori-Hayashi, Miho

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N2 - Background: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. Objective: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. Methods: Patch-clamp recordings from enhanced green fluorescent protein (EGFP)–expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. Results: We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9–mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. Conclusion: Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non–cell-autonomous mechanism involving LCN2 derived from reactive astrocytes.

AB - Background: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. Objective: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. Methods: Patch-clamp recordings from enhanced green fluorescent protein (EGFP)–expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. Results: We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9–mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. Conclusion: Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non–cell-autonomous mechanism involving LCN2 derived from reactive astrocytes.

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