Title:
Dorsal horn astrocytes: new player in chronic itch

 

Makoto Tsuda
Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University

 

Abstract:
Itch (or pruritus) is an unpleasant sensation that elicits the desire or reflex to scratch and normally serves as a self-protective mechanism from being hurt by harmful external agents such as parasites. However, under pathological conditions such as skin diseases like atopic dermatitis, itch becomes more severe and chronic, which leads to excessive, repetitive scratching. There is a rapidly growing body of evidence revealing the selective neuronal pathways for itch sensations. However, the mechanisms by which itching turns into a pathological chronic state are poorly understood. In this seminar, I will show our recent data demonstrating a new mechanism for chronic itch that involves the non-neuronal glial cells astrocytes in the spinal dorsal horn (SDH). In mouse models of atopic dermatitis, we show a long-term reactive state of astrocytes in the SDH segments that corresponds to lesioned, itchy skin. The transcription factor STAT3 was selectively activated in SDH astrocytes and that conditional disruption of astrocytic STAT3 activation prevented the astrocytic activation and chronic itching, without affecting acute physiological itch. Pharmacological inhibition of STAT3 in the SDH ameliorated the fully developed chronic itch. Furthermore, atopic dermatitis mice exhibited an increase in scratching elicited by intrathecal administration of gastrin-releasing peptide, and this enhancement was normalized by suppressing STAT3-mediated reactive astrocytes. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch. Therefore, our findings indicate that reactive astrocytes in the SDH with activated STAT3 play a pivotal role in chronic itch by enhancing spinal itch signaling by LCN2 and may represent a previously unrecognized target for treating chronic itch.

 

References:
Shiratori-Hayashi M et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat Med 21: 927-931 (2015).