Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis.
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.
Takuwa
T
Yasuda
Toshiyuki
T
Fukada
Keigo
K
Nishida
Manabu
M
Nakayama
Masashi
M
Matsuda
Ikuo
I
Miura
Teruki
T
Dainichi
Shinji
S
Fukuda
Kenji
K
Kabashima
Shinji
S
Nakaoka
Bum-Ho
BH
Bin
Masato
M
Kubo
Hiroshi
H
Ohno
Takanori
T
Hasegawa
Osamu
O
Ohara
Haruhiko
H
Koseki
Shigeharu
S
Wakana
Hisahiro
H
Yoshida
D019943:Amino Acid Substitution; D000818:Animals; D003872:Dermatitis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D003876:Dermatitis, Atopic / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D011537:Pruritus / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D015398:Signal Transduction; D012867:Skin / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D050505:Mutant Proteins; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1