Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis
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
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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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 2

Dermatitis is caused by a missense mutation in the Jak1 tyrosine kinase expressed in nonhematopoietic cells.

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Dermatitis is caused by a missense mutation in the Jak1 tyrosine kinase ...
(A and B) Detection of a Jak1 G-to-A point mutation in Jak1Spade/Spade-mutant mice (A) that replaces an arginine with a histidine at position 878 in the protein kinase domain of JAK1 (B). FERM, 4.1, ezrin, radixin, moesin; SH2, Src homology region 2. (C) Diagram of the Jak1R878H mutation knockin construct showing the location of the point mutation (red M in exon 19) and the selection cassette. (D) PCR amplification with the primers shown at the bottom of C was used to screen for homologous recombination in ES cells. (E) Southern blot of ES cell genomic DNA using the 5′ and 3′ probes depicted in panel C, confirming homologous recombination. (F) Physical appearance of a homozygous knockin mouse. (G) Photomicrographs showing histological sections of H&E- and TB-stained ear skin from a 20-week-old homozygous knockin mouse. Scale bars: 100 μm. Longitudinal analyses of dermatitis incidence (H) and clinical scores (I) of homozygous, heterozygous, and WT mice.