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 et al., 2018 Meng J. Moriyama M. Feld M. Buddenkotte J. Buhl T. Szöllösi A. et al. New mechanism underlying IL-31-induced atopic dermatitis. J Allergy Clin Immunol. 2018; 141: 1677-1689.e8 Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar ). Signal transducer and activator of transcription 6 (STAT6) is implicated in AD ( Howell et al., 2011 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. J Allergy Clin Immunol. 2011; 128: 1006-1014 Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar ) by acting as the upstream mediator of T helper 2 responses and promotes T helper 2 cell differentiation and phenotype ( Elo et al., 2010 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. Immunity. 2010; 32: 852-862 Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar ). Increased IL-4 and IL-13 exacerbate STAT6 transcription ( Howell et al., 2011 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. J Allergy Clin Immunol. 2011; 128: 1006-1014 Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar ; Kubo et al., 1997 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. EMBO J. 1997; 16: 4007-4020 Crossref PubMed Scopus (116) Google Scholar ), 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 et al., 2001 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. Oncogene. 2001; 20: 6660-6668 Crossref PubMed Scopus (87) Google Scholar ), a receptor implicated in AD ( Xiao et al., 2021 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. Brain Behav Immun. 2021; 98: 28-39 Crossref PubMed Scopus (8) Google Scholar ). IL-13 triggers STAT6 activation to upregulate periostin and IL-24 expression, promoting skin barrier dysfunction through the downregulation of FLG ( Mitamura et al., 2018 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. Allergy. 2018; 73: 1881-1891 Crossref PubMed Scopus (75) Google Scholar ). 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.