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Inhibiting Keratinocyte-Derived Signal Transducer and Activator of Transcription 6 Improved Atopic Dermatitis in Mice

      Pruritus is one of the most common symptoms in dermatology and is associated with significant patient morbidity, including atopic dermatitis (AD) (
      • Meng J.
      • Moriyama M.
      • Feld M.
      • Buddenkotte J.
      • Buhl T.
      • Szöllösi A.
      • et al.
      New mechanism underlying IL-31-induced atopic dermatitis.
      ). Signal transducer and activator of transcription 6 (STAT6) is implicated in AD (
      • Howell M.D.
      • Gao P.
      • Kim B.E.
      • Lesley L.J.
      • Streib J.E.
      • Taylor P.A.
      • et al.
      The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections.
      ) by acting as the upstream mediator of T helper 2 responses and promotes T helper 2 cell differentiation and phenotype (
      • Elo L.L.
      • Järvenpää H.
      • Tuomela S.
      • Raghav S.
      • Ahlfors H.
      • Laurila K.
      • et al.
      Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming.
      ). Increased IL-4 and IL-13 exacerbate STAT6 transcription (
      • Howell M.D.
      • Gao P.
      • Kim B.E.
      • Lesley L.J.
      • Streib J.E.
      • Taylor P.A.
      • et al.
      The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections.
      ;
      • Kubo M.
      • Ransom J.
      • Webb D.
      • Hashimoto Y.
      • Tada T.
      • Nakayama T.
      T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6.
      ), resulting in enhanced viral replication in patients with AD. IL-4 induces STAT6 activation in keratinocytes (KCs), resulting in an increased expression of IL-13Rα2 receptor chain (
      • David M.
      • Ford D.
      • Bertoglio J.
      • Maizel A.L.
      • Pierre J.
      Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways.
      ), a receptor implicated in AD (
      • Xiao S.
      • Lu Z.
      • Steinhoff M.
      • Li Y.
      • Buhl T.
      • Fischer M.
      • et al.
      Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis.
      ). IL-13 triggers STAT6 activation to upregulate periostin and IL-24 expression, promoting skin barrier dysfunction through the downregulation of FLG (
      • Mitamura Y.
      • Nunomura S.
      • Nanri Y.
      • Ogawa M.
      • Yoshihara T.
      • Masuoka M.
      • et al.
      The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation.
      ). However, the validity of targeting STAT6 for AD treatment has not been reported. To define the outcome of STAT6 inhibition in the alleviation of chronic itch and cutaneous inflammation, pharmacological inhibition was tested in this study in various murine chronic itch models.

      Abbreviations:

      AD (atopic dermatitis), EtOH (ethanol), KC (keratinocyte), STAT6 (signal transducer and activator of transcription 6)
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      Supplementary References

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        • Moriyama M.
        • Feld M.
        • Buddenkotte J.
        • Buhl T.
        • Szöllösi A.
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        J Allergy Clin Immunol. 2018; 141: 1677-1689.e8
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