CFTR-deficiency renders mice highly susceptible to cutaneous symptoms during mite infestation.
Pruritus, also known as itch, is a sensation that causes a desire to scratch. Prolonged scratching exacerbates skin lesions in several skin diseases such as atopic dermatitis. Here, we identify the cystic fibrosis transmembrane conductance regulator (CFTR/Cftr), an integral membrane protein that mediates transepithelial chloride transport, as a determinant factor in mice for the susceptibility to several cutaneous symptoms during mite infestation. Mice that endogenously express dysfunctional Cftr (Cftr(ΔF508/ΔF508)) show significant increase of scratching behavior and skin fibrosis after mite exposure. These phenotypes were due to the increased expression of nerve growth factor (NGF) that augments the sensitization of peripheral nerve fibers. Moreover, protein gene product 9.5 (PGP9.5)-positive neurites were abundant in the epidermis of mite-infested Cftr(ΔF508/ΔF508) mice. Furthermore, mite-infested Cftr(+/+) mice orally administered with a chloride channel inhibitor glibenclamide had higher scratching count and increased level of NGF than vehicle-treated mice. Consistently, mite extract-exposed primary and transformed human keratinocytes, treated with CFTR inhibitor, had significantly higher level of NGF mRNA compared with vehicle-treated, mite extract-exposed cells. These results reveal that CFTR in keratinocytes plays a critical role for the regulation of peripheral nerve function and pruritus sensation, and suggest that Cftr(ΔF508/ΔF508) mice may serve as a novel mouse model that represents NGF-dependent generation of pruritus.
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan.
Yasuaki
Y
Hashimoto
Tsuyoshi
T
Shuto
Shota
S
Mizunoe
Azusa
A
Tomita
Tomoaki
T
Koga
Takashi
T
Sato
Motohiro
M
Takeya
Mary Ann
MA
Suico
Akiko
A
Niibori
Takuya
T
Sugahara
Shogo
S
Shimasaki
Takashi
T
Sugiyama
Bob
B
Scholte
Hirofumi
H
Kai
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D004198:Disease Susceptibility; D005355:Fibrosis; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008924:Mite Infestations / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000473:pathology; D010525:Peripheral Nerves / Q000503:physiopathology; D010641:Phenotype; D011537:Pruritus / Q000209:etiology*; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000473:pathology
D018118:Chloride Channels; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D020932:Nerve Growth Factor; D005905:Glyburide