Papaioannou, Eleftheria; (2018) The role of Hedgehog signalling in atopic dermatitis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hedgehog (Hh) proteins are morphogens which regulate embryonic development and adult tissue homeostasis, with distinct outcomes dependent on the strength and duration of their signals. In skin, aberrant Hh pathway activation is linked to cancer and malformations, but the role of the pathway in skin inflammation remains largely unknown. Here I show that the Hh signalling pathway modulates the induction and pathology of mouse atopic dermatitis. Sonic hedgehog (Shh) and Hh pathway target genes were upregulated on induction of atopic dermatitis, and the Hh pathway was activated in skin T cells, showing that they respond in vivo to Hh signals secreted from the skin. Higher Shh upregulation reduced skin inflammation in mice, whereas pharmacological Smoothened-inhibition exacerbated skin pathology and reduced Shh upregulation. Hh-signalling to T cells prevented skin inflammation on induction of dermatitis, while inhibition of Hh-mediated transcription in T cells substantially exacerbated the disease. RNA-sequencing analysis of skin CD4+ T cells from mice with chronic atopic dermatitis revealed decreased expression of immune regulatory genes in mice with conditional inhibition of Hh-mediated transcription in T cells, and increased expression of inflammatory and chemokine genes. In contrast, constitutive Hh mediated transcription in T cells led to increased expression of immune regulatory genes in skin CD4+ T cells from mice with chronic atopic dermatitis and protected against inflammation. Hh-mediated transcription in T cells resulted in increased regulatory T (Treg) cells in the periphery and skin of dermatitis-induced mice, and increased TGF-β expression, supporting their immunoregulatory phenotype, whereas, inhibition of T cell specific Hh-mediated transcription, resulted in impaired Treg function, which permitted progression of skin inflammation. Thus, my data demonstrated a critical role for the Hh pathway through Shh upregulation, in the prevention of skin inflammation through upregulation of Shh signalling to T cells to increase Treg populations and promote their immunoregulatory function. This opens the possibility of novel therapeutic strategies for chronic inflammatory skin diseases and conversely suggests that Hh inhibitors could be used to enhance T cell immunity to Hh-secreting tumours.

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