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Selected Publication:
Borek, I.
Bone morphogenetic protein 7 (BMP7) aberrantly induced in psoriatic epidermis instructs inflammation-associated Langerhans cells.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 119
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- Authors Med Uni Graz:
- Advisor:
- Strobl Herbert
- Wolf Peter
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- Abstract:
- One of the hallmarks of psoriasis is the epidermal hyperplasia (acanthosis) caused by a strong proliferation of poorly differentiated keratinocytes (KCs). Several mouse models of psoriasis suggest a positive feedback loop between Langerhans cells (LCs) and keratinocytes (KCs), in instructing inflammatory epidermal microenvironment. Inflammation-associated LCs populate the psoriatic epidermis, where they engage with KCs in tight physical interactions. Moreover, LCs are potent inducers of T cell-mediated immune responses. However, mechanisms which instruct inflammatory LCs, and induce abnormal KCs expansion, are poorly defined. We demonstrated here that in the healthy human skin bone morphogenetic protein 7 (BMP7) expression is strictly confined to the basal KCs, whereas in the psoriatic lesional epidermis, high levels of BMP7 can be detected throughout epidermal layers. This epidermal BMP7 upregulation is accompanied by activation of its downstream signaling, i.e., pSmad1/5/8, in both KCs and LCs. In the in vitro model of LC differentiation, BMP7 induced generation of proliferating, CD1a+CD207+ cells with inflammatory characteristics: (1) up-regulation of inflammation-related genes, i.e., cytokines and chemokines, (2) high expression of CD1c, CD36 and CD206, (3) lack of Birbeck granules, (4) increased production of pro-inflammatory cytokines in response to microbial activation, and (5) strong capacity to stimulate CD4+ T cells. Furthermore, BMP signaling appears to be of functional importance for psoriatic lesion formation in vivo. Our analysis of two independent psoriasis mouse models showed that interference with BMP signaling, by intradermal injection of BMP antagonist noggin, results in decreased epidermal thickening and less pronounced swelling. Moreover, in psoriatic patients treated topically with dithranol, reduction of epidermal BMP7 expression correlates with clinical improvement. We propose a model, where a tight regulation of BMP7 within the epidermis is critical for KC and LC homeostasis. Aberrantly high BMP7 levels expressed by lesional psoriatic KCs promote epidermal changes, and induce differentiation of proliferative, inflammation-associated LCs. Therefore, targeting canonical BMP signaling may allow to therapeutically interfere with psoriatic skin manifestations.