STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch

Miho Shiratori-Hayashi, Keisuke Koga, Hidetoshi Tozaki-Saitoh, Yuta Kohro, Honami Toyonaga, Chiharu Yamaguchi, Ayumi Hasegawa, Takeshi Nakahara, Junichi Hachisuka, Shizuo Akira, Hideyuki Okano, Masutaka Furue, Kazuhide Inoue, Makoto Tsuda

Research output: Contribution to journalArticle

68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)927-931
Number of pages5
JournalNature medicine
Volume21
Issue number8
DOIs
Publication statusPublished - Aug 8 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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