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

Abstract

Background: Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. A strong IFN-g signature is characteristic for psoriasis skin, but the role of IFN-g 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-g-and/or TNF-related weak inducer of apoptosis (TWEAK)-treatment.Results: Here we report a microRNA-mediated mechanism by which IFN-g primes keratinocytes to inflammatory stimuli. Treatment with IFN-g 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-g-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-g primes keratinocytes for TWEAK-induced inflammatory

Homer1 promotes the conversion of A1 astrocytes to A2 astrocytes and improves the recovery of transgenic mice after intracerebral hemorrhage

“…In the present study, we found that the expression of TWEAK, activin A, and persephin was upregulated after Homer1 protein treatment. TWEAK, which is commonly involved in immune regulation, inflammation, and apoptotic processes, is a member of the TNF superfamily of cytokines [ 46 , 47 ] and it has been shown that crosstalk between IFN-γ and TWEAK amplifies skin inflammation in psoriasis through miR-149 [ 48 ]. Activin A is believed to be a pleiotropic cytokine with pro-inflammatory and anti-inflammatory properties [ 49 ].…”

Selenium-Rich Yeast Peptide Fraction Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis in Mice by Inhibiting Inflammation via MAPK and NF-κB Signaling Pathways

“…Previous studies suggested that the increased MAPK and NF-κB activation promote epidermal hyperproliferation and exacerbate psoriatic pathogenesis by triggering inflammatory responses [4,33,34]. Particularly, p38 MAPK over-phosphorylation breaks down the homeostasis of skin and induces cellular stresses, which might be the trigger of psoriasis dermatitis [35,36]. NF-κB, indicated by the p65 subunit nuclear translocation and phosphorylation as well as the IκBζ ablation, is the key component of IL-17 mediated skin inflammation [37,38].…”

The Expression Pattern of Genes Related to Melanogenesis and Endogenous Opioids in Psoriasis

“…This may result from elevated proinflammatory cytokines in psoriasis-TNF, IL-17, IL-1 and IL-6, which are known to inhibit melanogenesis and specifically PKA, MITF, TYR and DCT [ 12 , 14 , 30 ]. Likewise, another inflammatory cytokine associated with psoriasis, interferon gamma, has been shown to suppress CREB, MITF, p38 MAPK and melanogenesis [ 31 , 32 , 33 ]. These current findings are in agreement with our previous study where we found lowered expression of TYR and TYRP1 mRNA in psoriatic skin compared to healthy controls [ 16 ].…”