Involvement of thromboxane A2 in interleukin-31-induced itch-associated response in mice

저자	Andoh, Tsugunobu ⁎ Li, Sikai Uta, Daisuke
자료유형	Article
초록	•Interleukinin-31 (IL-31) induced scratching, an itch-associated response, in mice.•IL-31-induced scratching was inhibited by TP thromboxane (TX) receptor antagonist.•IL-31 receptors were expressed mainly in epidermal keratinocytes.•IL-31 induced TXA2 production in the skin and primary cultures of keratinocytes.•The results suggest that IL-31 elicits scratching via epidermal TXA2 production. Background Atopic dermatitis is a chronic and severe pruritic skin disease. Interlukin-31 (IL-31) has been recently demonstrated to be one of the key pruritogens in atopic dermatitis. However, the mechanisms underlying IL-31-induced itching remains unclear. In our previous study, we have shown that thromboxane (TX) A2 is involved in itch-associated responses in mice with atopy-like skin diseases. Methods IL-31 was given intradermally into the rostral back of ICR mice and the hind-paw scratching to the injection site were counted. Expression of TX synthase and IL-31 receptors were analyzed using immunohistochemical staining or RT-PCR in mouse skin or primary cultures of mouse keratinocytes. The concentration of TXB2, a metabolite of TXA2, in the skin and the culture medium of primary cultures of mouse keratinocytes was measured using enzyme immunoassay. The concentration of intracellular Ca2+ ions in mouse keratinocytes was measured using the calcium imaging method. Results An intradermal injection of IL-31 elicited scratching, an itch-related response, in mice. The scratching was inhibited by TP TXA2 receptor antagonist DCHCH. The distribution of TX synthase and IL-31RA receptor was mainly epidermal keratinocytes in the skin. The primary cultures of keratinocytes expressed the mRNAs of TX synthase and IL-31 receptors. IL-31 increased the concentration of TXB2, which was inhibited by TX synthase inhibitor sodium ozagrel and EGTA, in the skin and the culture medium of primary cultures of keratinocytes. IL-31 increased the concentration of intracellular Ca2+ ions in mouse keratinocytes. Conclusion It is suggested that IL-31 elicits itch-associated responses through TXA2 produced from keratinocytes.
Affiliation	Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
Publisher	Elsevier Urban & Partner Sp. z o.o.
DOI	10.1016/j.pharep.2017.10.001
Accession Number	S1734114017303808
Copyright	© 2017 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

 

Involvement of thromboxane A2 in interleukin-31-induced itch-associated response in mice

 

 

 

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

Landon K. Oetjen,1,2 Madison R. Mack,1,2 Jing Feng,1,3 Timothy M. Whelan,1,2 Haixia Niu,1,2 Changxiong J. Guo,1,3
Sisi Chen,4 Anna M. Trier,1,2 Amy Z. Xu,1,2 Shivani V. Tripathi,1,2 Jialie Luo,1,3 Xiaofei Gao,1,3 Lihua Yang,5
Samantha L. Hamilton,5 Peter L. Wang,6 Jonathan R. Brestoff,6 M. Laurin Council,2 Richard Brasington,7
Andra ́ s Schaffer,2,6 Frank Brombacher,8 Chyi-Song Hsieh,6,7 Robert W. Gereau IV,3 Mark J. Miller,5 Zhou-Feng Chen,1,3 Hongzhen Hu,1,3 Steve Davidson,4 Qin Liu,1,3 and Brian S. Kim1,2,3,6,9,*
1Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA
2Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
3Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
4Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
5Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA 6Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
7Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA 8International Centre for Genetic Engineering and Biotechnology and Institute of Infectious Disease and Molecular Medicine, Division of Immunology, University of Cape Town, Cape Town 7700, South Africa
9Lead Contact
*Correspondence: briankim@wustl.edu
http://dx.doi.org/10.1016/j.cell.2017.08.006

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also asso- ciated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mecha- nisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Ra and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies mark- edly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved para- digm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.