Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis

Sakurai, Kazuo; Dainichi, Teruki; Garcet, Sandra; Tsuchiya, Soken; Yamamoto, Yosuke; Kitoh, Akihiko; Honda, Tetsuya; Nomura, Takashi; Egawa, Gyohei; Otsuka, Atsushi; Nakajima, Saeko; Matsumoto, Reiko; Nakano, Yoshikatsu; Otsuka, Masayuki; Iwakura, Yoichiro; Grinberg‐Bleyer, Yenkel; Ghosh, Sankar; Sugimoto, Yukihiko; Guttman‐Yassky, Emma; Krueger, James G.; Kabashima, Kenji

doi:10.1016/j.jaci.2019.06.019

Cited by 46 publications

(30 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Western blot analysis showed that phosphorylation of p38 in skin was induced after IMQ application (Fig 5, H), which is consistent with increased p38 phosphorylation in human psoriasis lesions. [36][37][38] In line with the results obtained with human keratinocytes, delivery of synthetic miR-149 suppressed IMQ-induced phosphorylation of p38 in mouse skin (Fig 5, H).…”

Section: Mir-149 Suppresses Tweak Signaling By Targeting Tweakrsupporting

confidence: 87%

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

Srivastava

Luo

Lohcharoenkal

et al. 2021

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

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

show abstract

Section: Mir-149 Suppresses Tweak Signaling By Targeting Tweakrsupporting

confidence: 87%

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

Srivastava

Luo

Lohcharoenkal

et al. 2021

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…Psoriasis is a recurrent, chronic skin disease with complex immune-inflammatory ethology (Nestle et al, 2009;Sakurai et al, 2019). The worldwide prevalence of psoriasis is about 3% and the high societal burden of this condition is mainly due to the substantial impact on the patients' perception of confidence and well-being (Lowes et al, 2007;Greb et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Biotechnologically Produced Lavandula angustifolia Mill. Extract Rich in Rosmarinic Acid Resolves Psoriasis-Related Inflammation Through Janus Kinase/Signal Transducer and Activator of Transcription Signaling

et al. 2021

View full text Add to dashboard Cite

Psoriasis is a common skin pathology, characterized by dysregulation of epidermal keratinocyte function attended by persistent inflammation, suggesting that molecules with anti-inflammatory potential may be effective for its management. Rosmarinic acid (RA) is a natural bioactive molecule known to have an anti-inflammatory potential. Here we examined the effect of biotechnologically produced cell suspension extract of Lavandula angustifolia Mill (LV) high in RA content as treatment for psoriasis-associated inflammation in human keratinocytes. Regulatory genes from the nuclear factor kappa B (NF-κB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways were upregulated upon stimulation with a combination of interferon gamma (IFN-γ), interleukin (IL)-17A and IL-22. We also observed that both LV extract and RA could inhibit JAK2, leading to reduced STAT1 phosphorylation. Further, we demonstrated that LV extract inhibited phosphoinositide 3-kinases (PI3K) and protein kinase B (AKT), which could be implicated in reduced hyperproliferation in keratinocytes. Collectively, these findings indicate that the biotechnologically produced LV extract resolved psoriasis-like inflammation in human keratinocytes by interfering the JAK2/STAT1 signaling pathway and its effectiveness is due to its high content of RA (10%). Hence, both LV extract and pure RA possess the potential to be incorporated in formulations for topical application as therapeutic approach against psoriasis.

show abstract

“…However, in that study the characterization of the psoriasis phenotype was limited to evaluation of the histological features of the tissue at day 0 and 8. Others have also reported the use of ex vivo culture of psoriasis skin for testing effects of anti-inflammatory compounds [10,11]. However, in these studies characterization of the psoriasis phenotype upon ex vivo culture was not described and the culture time was shorter compared to our model, limiting the feasibility to investigate effects by anti-inflammatory compounds [10,11].…”

Section: Discussionmentioning

confidence: 94%

“…Others have also reported the use of ex vivo culture of psoriasis skin for testing effects of anti-inflammatory compounds [10,11]. However, in these studies characterization of the psoriasis phenotype upon ex vivo culture was not described and the culture time was shorter compared to our model, limiting the feasibility to investigate effects by anti-inflammatory compounds [10,11]. On the contrary, we demonstrated that the time frame in our model is sufficient to see treatment effects of both a small molecule and an antibody.…”

Section: Discussionmentioning

confidence: 99%

“…The major challenges of these models are associated with incorporation of immune cells of specific phenotype of relevance in psoriasis, as well as with replicating the histopathological features of psoriasis [9]. Short term (12À14 hrs) ex vivo culture of psoriasis skin for test of anti-inflammatory compounds has previously been reported by others, but a characterization of the psoriasis phenotype upon ex vivo culture has not been included [10,11].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ex vivo culture of lesional psoriasis skin for pharmacological testing

Tiirikainen

Woetmann

Norsgaard

et al. 2020

Journal of Dermatological Science

View full text Add to dashboard Cite

Background: Psoriasis is a chronic, inflammatory skin disorder resulting from a complex interplay between immune and skin cells via release of soluble mediators. While a lot is known about the molecular mechanisms behind psoriasis pathogenesis, there is still a need for preclinical research models that accuratelyreplicate the disease.Objective: This study aimed to develop and characterize ex vivo culture of psoriasis skin as a model for pharmacological testing, where the immunological events of psoriasis can be followed. Methods: Full thickness punch biopsies of lesional psoriasis skin were cultured in submerged conditions up to 144 h followingin situ T cell stimulation with rhIL-23 and anti-CD3 and anti-CD28 antibodies. The T cell mediated skin inflammation was assessed by gene and protein l analysis for a panel of inflammatory mediators. Tissue integrity and morphology were evaluated by histological analysis. Results: T cell stimulation resulted in functional and psoriasis specificin situ activation of T cells. The expression levels of most of the proinflammatory mediators related to both immune and skin cells were comparable to these in freshly isolated tissue at 48 and 96 h of culture. Tissue integrity and morphology were sustained up to 96 h. Treatment with a corticosteroid reduced the expression of several proinflammatory cytokines and chemokines, whereas anti-IL-17A antibody treatment reduced the expression of the IL-17A downstream markers IL-8 and DEFB4. Conclusion: By preserving keyimmunopathological mechanisms of psoriasis, ex vivo culture of psoriasis skin can be used for the investigation of inflammatory processes of psoriasis and for preclinical drug discovery research.

show abstract

Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis

Cited by 46 publications

References 49 publications

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

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

Biotechnologically Produced Lavandula angustifolia Mill. Extract Rich in Rosmarinic Acid Resolves Psoriasis-Related Inflammation Through Janus Kinase/Signal Transducer and Activator of Transcription Signaling

Ex vivo culture of lesional psoriasis skin for pharmacological testing

Contact Info

Product

Resources

About