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.
Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of Smo, Il4, Il13, and the mucin gene Muc5ac in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway.
PURPOSE. Bardet-Biedl syndrome (BBS) is an archetypical ciliopathy caused by defective ciliary trafficking and consequent function. Insights gained from BBS mouse models are applicable to other syndromic and nonsyndromic retinal diseases. This progressive characterization of the visual phenotype in three BBS mouse models sets a baseline for testing therapeutic interventions. METHODS. Longitudinal acquisition of electroretinograms, optical coherence tomography scans, and visual acuity using the optomotor reflex in Bbs6/Mkks, Bbs8/Ttc8, and Bbs5 knockout mice. Gene and protein expression analysis in vivo and in vitro. RESULTS. Complete loss of BBS5, BBS6, or BBS8 leads to different rates of retinal degeneration and visual function over time. BBS8-deficient mice showed the fastest rate of degeneration, and BBS8 seems to be required for cone photoreceptors to reach functional maturity. In contrast, the loss of BBS5 (a further BBSome component) showed very little degeneration. Loss of BBS8 versus BBS5 resulted in different physiologic responses both in vivo and in vitro. BBS6-deficient mice show a slower rate of degeneration with both rod and cone function reducing at a similar rate. CONCLUSIONS. The mouse models analyzed show distinct and diverging courses of degeneration upon loss of BBS5, BBS6, or BBS8, which can be used as a benchmark to test therapeutic interventions. Close consideration of the different phenotypes reveal subtle but important differences relating to their function. Because we also see differences in terms of phenotype depending on the type of visual assessment used, our data highlight the importance of using a combinatorial approach for assessment of visual function.
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