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

Ankit Srivastava1, Longlong Luo1, Warangkana Lohcharoenkal1

  • 1Dermatology and Venereology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden.

The Journal of Allergy and Clinical Immunology
|March 11, 2021
PubMed
Abstract

Insights

Interferon-gamma (IFN-γ) suppresses miR-149 in skin cells, amplifying inflammation. Restoring miR-149 offers a protective effect in psoriasis models, revealing a new therapeutic target.

Area of Science:

  • Dermatology
  • Immunology
  • Molecular Biology

Background:

  • Psoriasis is a chronic inflammatory skin condition characterized by immune cell and keratinocyte dysregulation.
  • A significant interferon-gamma (IFN-γ) signature is observed in psoriatic skin, though its precise role remains unclear.
  • MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in various diseases.

Purpose of the Study:

  • To investigate the role of miR-149 in the pathogenesis of psoriasis.
  • To elucidate the function of miR-149 in keratinocyte inflammatory responses.
  • To explore the interaction between IFN-γ, miR-149, and the TWEAK pathway in skin inflammation.

Main Methods:

  • Quantitative RT-PCR was used to measure miR-149 expression in human keratinocytes from healthy and psoriatic skin.
  • A mouse model of imiquimod-induced psoriasis-like skin inflammation was utilized, with intradermal injections of synthetic miR-149.
  • miR-149 was manipulated (overexpressed or inhibited) in keratinocytes treated with IFN-γ and/or TWEAK.

Main Results:

  • IFN-γ treatment rapidly and persistently suppressed miR-149 expression in keratinocytes.
  • miR-149 depletion in keratinocytes induced transcriptomic changes and inflammatory mediators, particularly involving the TWEAK pathway.
  • IFN-γ-induced suppression of miR-149 potentiated keratinocyte inflammatory responses to TWEAK, with TWEAKR/Fn14 identified as a direct miR-149 target.
  • Reduced miR-149 expression was observed in psoriatic skin, and synthetic miR-149 demonstrated protective effects in the mouse model.

Conclusions:

  • A novel mechanism is identified where IFN-γ primes keratinocytes for TWEAK-induced inflammation by suppressing miR-149.
  • This miR-149 suppression promotes skin inflammation, highlighting its significance in psoriasis pathogenesis.
  • Targeting the miR-149 pathway presents a potential therapeutic strategy for managing psoriasis and related inflammatory skin conditions.
Keywords:
IFN-γIFN-γ–mediated primingPsoriasisTWEAK/TWEAKR pathwaycytokineskeratinocytesmicroRNAsskin inflammation

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