title: STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch.
abstract: Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis. Recent studies have revealed neuronal pathways selective for itch, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.
authors.affiliation: 1] Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [2] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Shiratori-Hayashi
authors.affiliation: 1] Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [2] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Koga
authors.affiliation: 1] Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [2] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tozaki-Saitoh
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kohro
authors.affiliation: 1] Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [2] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Toyonaga
authors.affiliation: 1] Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [2] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakahara
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hachisuka
authors.affiliation: 1] Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan. [2] Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.affiliation: 1] Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. [2] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
mesh_terms: D000209:Acute-Phase Proteins / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002908:Chronic Disease; D019886:Gastrin-Releasing Peptide / Q000502:physiology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000502:physiology; D011537:Pruritus / Q000209:etiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D066148:Spinal Cord Dorsal Horn / Q000473:pathology*
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C071332:Lcn2 protein, mouse; D019886:Gastrin-Releasing Peptide