Abstract
Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor–β (TGF-β) in Treg signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4+ T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4+ T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven, Treg cell–mediated immune suppression, paving the way for a potential new therapeutic strategy.
Highlights
Skin is in direct contact with the environment and acts as protective barrier from mechanical injuries and infections
We demonstrate that Sonic Hedgehog (Shh) signaling regulates the skin T cell immune response in atopic dermatitis (AD)
Cross-talk between epithelial cells and lymphocytes is essential for maintenance of skin homeostasis, and disruption of skin barrier function together with immune dysregulation lead to AD
Summary
Skin is in direct contact with the environment and acts as protective barrier from mechanical injuries and infections. The mechanisms that cause AD remain controversial, but Filaggrin, a terminal differentiation marker of keratinocytes, is important for skin barrier formation, and its deficiency promotes immune alterations which contribute to AD [2]. Skin inflammation in AD changes through time, with expanded T helper 2 (Th2) and Th17 responses at early stages, and a partial switch to a Th1 response during chronic stages [1,2,3]. CD4+CD25+Foxp3+ Tregs are abundant in skin, and in inflammation they infiltrate the dermis but lose their immunoregulatory function, further enhancing the inflammatory response [1, 4,5,6,7,8]. The reasons why the CD4+CD25+Foxp3+ population in skin fails to suppress the immune response in AD is unclear, so identification of skin factors that promote immune regulation is important to preventing AD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
