Type 2 cytokine-JAK1 signaling is involved in the development of dry-skin induced mechanical alloknesis
Yui Toyosawa ab, Eriko Komiya ac, Eriko Komiya ac, Takahide Kaneko b, Yasushi Suga b, Mitsutoshi Tominagaa, Kenji Takamori aba
aJuntendo Itch Research Center (JIRC), Institute for Environmental and Gender- Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan
bDepartment of Dermatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan
cDepartment of Functional Morphology, Faculty of Pharmacy, Juntendo University, 6-8-1 Hinode, Urayasu, Chiba 279-0013, Japan
Received 8 March 2024, Revised 2 October 2024, Accepted 18 October 2024, Available online 22 October 2024.
Abstract
Background
Mechanical alloknesis (m-alloknesis) is itch hypersensitivity induced by normally innocuous stimuli. It is sometimes observed in dry skin based itch-related diseases such as atopic dermatitis (AD), and often triggers the vicious itch-scratch cycle. The acetone-ether and water (AEW) mouse model mimics dry skin induced m-alloknesis, yet its underlying mechanism remains unclear. Janus kinase (JAK) inhibitors are used to treat AD, but their effects on m-alloknesis are not fully known.
Objective
To reveal the effects of various oral JAK inhibitors on m-alloknesis and their action points, using AEW model.
Methods
AEW model was prepared by treatment with a mixture of acetone-ether, and they were orally administrated a JAK1/2 inhibitor baricitinib, a selective JAK1 inhibitor abrocitinib, or a JAK2 selective inhibitor AZ960, and evaluated m-alloknesis score as the total number of scratching responses in 30 mechanical stimulations. To further elucidate the mechanism of action, IL-4, IL-13 or thymic stromal lymphopoietin (TSLP) or their neutralizing antibodies were also applied to mice. In addition, the levels of these cytokines in mouse skin were measured using multiple immunoassays.
Results
All of JAK inhibitors effectively reduced m-alloknesis, with abrocitinib demonstrating the most significant inhibition. The neutralizing antibodies against IL-4, IL-13, and TSLP inhibited m-alloknesis in AEW mice. Intradermal administration of IL-4, IL-13, or TSLP induced m-alloknesis, and abrocitinib effectively mitigated each cytokine-induced response. Highly sensitive assays detected IL-4, IL-13, IL-31 and TSLP in AEW-treated skin, with TSLP levels significantly increased.
Conclusion
Type 2 cytokine-JAK1 signaling is involved in the development of m-alloknesis in dry skin.
Abbreviations
AD, atopic dermatitis; AEW, acetone-ether and water; IL, interleukin; ILC2, group 2 innate lymphoid cells; JAK, Janus kinase; m-alloknesis, mechanical alloknesis; NT, non-treated; SC, stratum corneum; STAT, signal transducer and activator of transcription; TEWL, transepidermal water loss; Th2, type 2 T helper cells; TSLP, thymic stromal lymphopoietin; W, water
Keywords
atopic dermatitis, dry skin, JAK inhibitors, mechanical alloknesis,mechanical itch, Th2 cytokines
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