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RAGE as a regulatory molecule in cutaneous chronic inflammation

Tarnanidis, Kathrin

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Psoriasis is a complex genetic, chronic inflammatory disease of the skin with a prevalence of 2 % among the population. It is characterized by a multi-faceted interplay of keratinocytes, dendritic and T cells, as well as downstream transcription factors and proinflammatory cytokines. The IL-23/TH17 axis is thought to play an important role in the pathogenesis of psoriasis. However, the relative contributions of keratinocytes and immune cells to disease initiation and maintenance remain unclear. Recent studies implicate a role of the receptor for advanced glycation end-products (aptly known as RAGE) in the development of chronic disorders due to its expression on involved cell types and its constitutive signaling in inflammatory conditions. The here presented thesis revealed a role for RAGE in psoriasis by demonstrating its upregulation in human and murine psoriatic specimens. In addition, RAGE drives and maintains chronic inflammation as the initial phase and the chronic stage of the inflammation were found to be diminished in Rage-deficient mice upon topical Imiquimod treatment. Moreover, RAGE was expressed on psoriatic effector cells such as keratinocytes and dermal inflammatory cells including CD11c+ dendritic cells. While the inflammation-associated activation of keratinocytes resulting in a release of the alarmins S100B and HMGB1 was demonstrated to be independent of RAGE, the functionality of plasmacytoid dendritic cells, which are major activators of dermal dendritic cells, strongly relied on active RAGE signaling. Indeed, both HMGB1 and S100B in complex with self-DNA activated plasmacytoid dendritic cells via RAGE. The finding that RAGE additionally controls the transcription of inflammatory response genes involved in the differentiation of naïve T cells into the T helper cell lineage further supported the hypothesis that RAGE signaling is essential for the activation of the IL-23/TH17 axis in psoriasis. This was underlined by the rescue of the defective inflammatory phenotype of Rage-deficient mice by intradermal injections of recombinant IL-23. Taken together, these findings illustrate an epidermal-innate immune crosstalk mediated by RAGE signaling that in turn affects adaptive immune responses and points towards a central role of RAGE in the IL-23/TH17 axis of psoriasis. Therefore, this thesis highlights RAGE signaling as a potential target for new therapeutic strategies intervening ‘upstream’ of IL-23.

Item Type: Dissertation
Supervisor: Umansky, Prof. Dr. Viktor
Date of thesis defense: 25 November 2015
Date Deposited: 08 Dec 2015 09:12
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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