Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation

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.

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

“…This is supported by previous studies showing that Sonic HH/GLI signaling can induce IL10 expression in a murine model of colitis and pancreatitis. Similarly, overexpression of active GLI2 in T cells can cell‐autonomously enhance IL10 and TGFβ expression [66–69]. In line with the expression of IL10 and TGFβ, we show increased numbers of Treg cells in Ptch Δep tumors, similar to human BCC, where Omland et al .…”

The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

“…Biolegend, (San Diego, US), acquired on C6Accuri (BD-Biosciences) or Cytoflex (BeckmanCoulter) and analysed using Flowjo10.6 (TreeStar, US). Intracellular staining was as described (Papaioannou et al, 2019). Apoptosis was measured using AnnexinV-FITC (eBioscience) and Annexin binding buffer (Biolegend, San Diego, USA) as described (Shah et al, 2004).…”

The IFITM protein family in adaptive immunity

“…In atopic dermatitis patients, IFITM1-3 are up-regulated in lesional skin compared with non-lesional skin from the same individuals, although the functional consequences of their increased expression have not been investigated. 78 Likewise, their expression is up-regulated in inflamed mucosa of ulcerative colitis and Crohn's disease patients, 43,79 and polymorphisms in IFITM1 and IFITM3 are associated with increased susceptibility to ulcerative colitis. 80,81 In mice, the IFITM family protect against colitis.…”