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MicroRNAs in skin immunity and psoriasis

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posted on 2024-09-02, 19:13 authored by Florian Meisgen

The skin protects the organism from the environment and shields it from the constant danger of infections by microorganisms. Keratinocytes are epithelial cells in the skin that constitute a physical barrier towards the environment. More than that, they are essential players in innate immunity: Keratinocytes can recognize invading pathogens by a variety of receptors, among them Toll-like receptors (TLRs). Activation of keratinocytes by pathogenic triggers leads to the induction of an inflammatory reaction in the skin, finally leading to the destruction and elimination of the pathogens. After clearance of the infection, homeostasis needs to be restored in order to avoid pathophysiological chronic inflammation. Psoriasis is a common chronic inflammatory skin disease characterized by local and systemic activation of both the innate and the adaptive immune system. In psoriasis skin lesions, hyperproliferation and activation of keratinocytes is combined with a massive infiltration of immune cells into the skin. MicroRNAs are endogenous short RNA molecules that regulate gene expression at the posttranscriptional level. They have been shown to be involved in the regulation of all basic biological processes. The aim of this thesis was to study the role of microRNAs in skin immunity, with a focus on their regulation and function in keratinocytes under homeostatic and inflammatory conditions.

We have characterized systematically the microRNA expression profile of keratinocytes treated with ligands for TLR2, TLR5 and TLR3, showing that a distinct subset of microRNAs is regulated by different TLR ligands (Paper I). MiR-146a was strongly induced by all studied TLR ligands, while other microRNAs were regulated in a TLR- or time pointspecific manner. A detailed analysis of the regulation of miR-146a in keratinocytes revealed its long-lasting induction upon TLR2 stimulation, leading to a global repression of the inflammatory response (Paper II). Functionally, miR-146a acts as a negative feedback to counteract TLR2-induced inflammation and to restore tissue homeostasis by suppressing the production of inflammatory mediators and the chemotactic attraction of immune cells. Moreover, endogenous miR-146a was essential to prevent unstimulated keratinocytes from producing inflammatory mediators, thus protecting from unwanted inflammation in the absence of a trigger. In the chronically inflamed skin of psoriasis patients, miR-146a was overexpressed and keratinocytes were partially responsible for this phenotype (Paper III). Pro-inflammatory cytokines of the IL-1 family were shown to be strong inducers of miR-146a, plausibly responsible for the miR-146a overexpression in psoriasis keratinocytes. Taken together, these results propose that miR-146a regulates skin immune responses after infection or skin injury and may set the threshold of activation in keratinocytes. We have identified miR-31 as another microRNA overexpressed in psoriasis keratinocytes and regulating the keratinocyte immune responses (Paper IV). MiR-31 could be induced by TGF-β1 in vitro and in vivo. Inhibition of endogenous miR-31 decreased the inflammatory activity of keratinocytes, suggesting that miR-31 acts as a pro-inflammatory microRNA and contributes to the chronic inflammation in psoriasis lesions.

In conclusion, the data presented in this thesis underline the crucial importance of microRNAs in the innate immune response of keratinocytes. The modulation of the local inflammatory environment by microRNAs may explain more of the unknown underlying factors regulating susceptibility to autoimmune diseases such as psoriasis.

List of scientific papers

I. Activation of Toll-like receptors alters the microRNA expression profile of keratinocytes. Florian Meisgen, Ning Xu Landén, Charbel Bouez, Michela Zuccolo, Audrey Gueniche, Mona Ståhle, Enikö Sonkoly, Lionel Breton and Andor Pivarcsi. Experimental Dermatology. 2014 Apr;23(4):281-3.
https://doi.org/10.1111/exd.12361

II. MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes. Florian Meisgen, Ning Xu Landén, Aoxue Wang, Bence Réthi, Charbel Bouez, Michela Zuccolo, Audrey Gueniche, Mona Ståhle, Enikö Sonkoly, Lionel Breton and Andor Pivarcsi. Journal of Investigative Dermatology. 2014 Jul;134(7):1931-40.
https://doi.org/10.1038/jid.2014.89

III. MiR-146a is up-regulated in psoriasis and acts as a negative feedback on IL-36 and IL-1β signaling in keratinocytes. Florian Meisgen, Ankit Srivastava, Ning Xu Landén, Mona Ståhle, Andor Pivarcsi and Enikö Sonkoly. [Manuscript]

IV. MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40. Ning Xu, Florian Meisgen, Lynn Butler, Gangwen Han, Xiao-Jing Wang, Cecilia Söderberg-Nauclér, Mona Ståhle, Andor Pivarcsi and Enikö Sonkoly. The Journal of Immunology. 2013 Jan 15;190(2):678-88.
https://doi.org/10.4049/jimmunol.1202695

History

Defence date

2015-01-23

Department

  • Department of Medicine, Solna

Publisher/Institution

Karolinska Institutet

Main supervisor

Sonkoly, Enikö

Publication year

2014

Thesis type

  • Doctoral thesis

ISBN

978-91-7549-763-1

Number of supporting papers

4

Language

  • eng

Original publication date

2014-12-16

Author name in thesis

Meisgen, Florian

Original department name

Department of Medicine, Solna

Place of publication

Stockholm

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