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Cross-talk between ...
Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis
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- Srivastava, Ankit (author)
- Karolinska Institutet
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- Luo, Longlong (author)
- Karolinska Institutet
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Lohcharoenkal, Warangkana (author)
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Meisgen, Florian (author)
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Pasquali, Lorenzo (author)
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- Pivarcsi, Andor (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Karolinska institutet
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- Sonkoly, Enikö (author)
- Karolinska Institutet,Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Unit of Dermatology, Karolinska University Hospital, Stockholm, Sweden
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(creator_code:org_t)
- Elsevier, 2021
- 2021
- English.
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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 147:6, s. 2225-2235
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Abstract
Subject headings
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- BACKGROUND: Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. A strong IFN-γ signature is characteristic for psoriasis skin, but the role of IFN-γ 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-γ- and/or TNF-related weak inducer of apoptosis (TWEAK)-treatment.RESULTS: Here we report a microRNA-mediated mechanism by which IFN-γ primes keratinocytes to inflammatory stimuli. Treatment with IFN-γ 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-γ-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-γ primes keratinocytes for TWEAK-induced inflammatory responses through suppression of miR-149, promoting skin inflammation.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- IFN-γ
- IFN-γ–mediated priming
- Psoriasis
- TWEAK/TWEAKR pathway
- cytokines
- keratinocytes
- microRNAs
- skin inflammation
Publication and Content Type
- ref (subject category)
- art (subject category)
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