Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis
Takuwa Yasuda, … , Shigeharu Wakana, Hisahiro Yoshida
Takuwa Yasuda, … , Shigeharu Wakana, Hisahiro Yoshida
Published June 1, 2016; First published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2064-2076. https://doi.org/10.1172/JCI82887.
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Research Article Dermatology

Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

Abstract

Skin homeostasis is maintained by the continuous proliferation and differentiation of epidermal cells. The skin forms a strong but flexible barrier against microorganisms as well as physical and chemical insults; however, the physiological mechanisms that maintain this barrier are not fully understood. Here, we have described a mutant mouse that spontaneously develops pruritic dermatitis as the result of an initial defect in skin homeostasis that is followed by induction of a Th2-biased immune response. These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function. Accordingly, treatment with an ointment to maintain normal skin barrier function protected mutant mice from dermatitis onset. Pharmacological inhibition of JAK1 also delayed disease onset. Together, these findings indicate that JAK1-mediated signaling cascades in skin regulate the expression of proteases associated with the maintenance of skin barrier function and demonstrate that perturbation of these pathways can lead to the development of spontaneous pruritic dermatitis.

Authors

Takuwa Yasuda, Toshiyuki Fukada, Keigo Nishida, Manabu Nakayama, Masashi Matsuda, Ikuo Miura, Teruki Dainichi, Shinji Fukuda, Kenji Kabashima, Shinji Nakaoka, Bum-Ho Bin, Masato Kubo, Hiroshi Ohno, Takanori Hasegawa, Osamu Ohara, Haruhiko Koseki, Shigeharu Wakana, Hisahiro Yoshida

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Figure 6

Dermatitis in Spade-mutant mice is due to a defect in skin barrier function that coincides with abnormal expression of serine proteases in mutant skin.

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Dermatitis in Spade-mutant mice is due to a defect in skin barrier funct...
(A) Longitudinal analysis of the TEWL rate in the ear skin of Jak1Spade/Spade, Jak1+/Spade, and WT mice. Error bars represent the mean ± SD of 6 mice per group. *P < 0.05, by 1-way ANOVA, followed by Bonferroni’s test. (B) Fluorescence micrographs showing the infiltration of biotin particles into the skin of 6-week-old Jak1Spade/Spade and WT mice. Scale bars: 20 μm. (C and D) Longitudinal analyses of dermatitis incidence (C) and clinical scores (D) in mice treated from 4 weeks to 14 weeks of age with a topical application of petrolatum 3 times per week. Data represent the mean ± SD of 8 mice per group. *P < 0.05 and ***P < 0.001, relative to nontreated Jak1Spade/Spade mice, by Mann-Whitney U test. (E) Longitudinal analysis of TEWL in Jak1Spade/Spade mice treated with a topical application of petrolatum or left untreated as a control. Each circle represents the TEWL level of an individual mouse, and white circles and black circles represent nondiseased and diseased mice, respectively. Error bars represent the mean ± SD of 6 mice per group. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test.