Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:147

Article

Srivastava, Ankit¹  Luo, Longlong¹  Lohcharoenkal, Warangkana¹  Meisgen, Florian¹  Pasquali, Lorenzo¹  Pivarcsi, Andor^1,2  Sonkoly, Eniko^1,3 

[1] Karolinska Inst, Dept Med Solna, Dermatol & Venereol Div, CMM L8 02, S-17176 Stockholm, Sweden

[2] Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden

[3] Karolinska Univ Hosp, Unit Dermatol, Stockholm, Sweden

关键词: Psoriasis;    skin inflammation;    keratinocytes;    microRNAs;    cytokines;    IFN-gamma;    IFN-gamma-mediated priming;    TWEAK/TWEAKR pathway;   

DOI  :  10.1016/j.jaci.2020.12.657

来源: Elsevier

【 摘 要 】

Background: Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. A strong IFN-gamma signature is characteristic for psoriasis skin, but the role of IFN-gamma has been elusive. MicroRNAs are short RNAs regulating gene expression. Objective: Our aim was to investigate the role of miR-149 in psoriasis and in the inflammatory responses of keratinocytes. Methods: miR-149 expression was measured by quantitative RT-PCR in keratinocytes isolated from healthy skin and lesional and nonlesional psoriasis skin. Synthetic miR-149 was injected intradermally into the back skin of mice, and imiquimod was applied to induce psoriasis-like skin inflammation, which was then evaluated at the morphologic, histologic, and molecular levels. miR-149 was transiently overexpressed or inhibited in keratinocytes in combination with IFN-gamma- and/or TNF-related weak inducer of apoptosis (TWEAK)-treatment. Results: Here we report a microRNA-mediated mechanism by which IFN-gamma primes keratinocytes to inflammatory stimuli. Treatment with IFN-gamma results in a rapid and long-lasting suppression of miR-149 in keratinocytes. Depletion of miR-149 in keratinocytes leads to widespread transcriptomic changes and induction of inflammatory mediators with enrichment of the TWEAK pathway. We show that IFN-gamma-mediated suppression of miR-149 leads to amplified inflammatory responses to TWEAK. TWEAK receptor (TWEAKR/Fn14) is identified as a novel direct target of miR-149. The in vivo relevance of this pathway is supported by decreased miR-149 expression in psoriasis keratinocytes, as well as by the protective effect of synthetic miR-149 in the imiquimod-induced mouse model of psoriasis. Conclusion: Our data define a new mechanism, in which IFN-gamma primes keratinocytes for TWEAK-induced inflammatory responses through suppression of miR-149, promoting skin inflammation.

【 授权许可】

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