Advances in the pathogenesis of psoriasis: from keratinocyte perspective

Zhou, Xue; Chen, Youdong; Cui, Lian; Shi, Yu; Guo, Chunyuan

doi:10.1038/s41419-022-04523-3

Cited by 270 publications

(153 citation statements)

References 147 publications

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“…Psoriasis is an autoimmune disease mediated by overactive IL17 secreting type 17 T-cells (such as Th17 and Tc17) and defective negative regulatory networks (such as dysfunctional Tregs). Many researchers have focused on immune-related factors in the development of psoriasis, but haveignored the cell-fate transition of hyperproliferative keratinocytes themselves [31]. As part of this work, scRNA-seq analysis of psoriasis and control skin-derived cells were performed to identify the cell fate transition of nonimmune subsets (Additional file 1: Fig.…”

Section: Imbalances Of Ferroptosis and Pyroptosis Involved In The Dev...mentioning

confidence: 99%

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Zhang

et al. 2022

J Transl Med

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Background Approximately 8–9% of the world’s population is affected by autoimmune diseases, and yet the mechanism of autoimmunity trigger is largely understudied. Two unique cell death modalities, ferroptosis and pyroptosis, provide a new perspective on the mechanisms leading to autoimmune diseases, and development of new treatment strategies. Methods Using scRNA-seq datasets, the aberrant trend of ferroptosis and pyroptosis-related genes were analyzed in several representative autoimmune diseases (psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn’s disease, and experimental autoimmune orchitis). Cell line models were also assessed using bulk RNA-seq and qPCR. Results A substantial difference was observed between normal and autoimmune disease samples involving ferroptosis and pyroptosis. In the present study, ferroptosis and pyroptosis showed an imbalance in different keratinocyte lineages of psoriatic skinin addition to a unique pyroptosis-sensitive keratinocyte subset in atopic dermatitis (AD) skin. The results also revealed that pyroptosis and ferroptosis are involved in epidermal melanocyte destruction in vitiligo. Aberrant ferroptosis has been detected in multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn’s disease, and autoimmune orchitis. Cell line models adopted in the study also identified pro-inflammatory factors that can drive changes in ferroptosis and pyroptosis. Conclusion These results provide a unique perspective on the involvement of ferroptosis and pyroptosis in the pathological process of autoimmune diseases at the scRNA-seq level. IFN-γ is a critical inducer of pyroptosis sensitivity, and has been identified in two cell line models.

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Section: Imbalances Of Ferroptosis and Pyroptosis Involved In The Dev...mentioning

confidence: 99%

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Zhang

et al. 2022

J Transl Med

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“…It is characterized by an abnormal cell cycle of epidermal cells that leads to epidermal hyperproliferation and altered maturation of these cells, vascular alterations, and inflammation [1,2]. The pathogenesis of psoriasis is highly complex, that includes keratinocytes, inflammatory cells, pro-inflammatory cytokines, and growth factors [3,4]. Recently published data have delivered new understandings of the cellular and molecular pathways involved in the pathogenesis of psoriasis.…”

Section: Introductionmentioning

confidence: 99%

Modulatory Effects of Leave and Fruit Extracts of Ficus sycomorus on Cytostatic and Inflammatory Mediators in Monocultures and Co-cultures of Human Keratinocyte (HaCat) and Human Monocyte (THP-1) Cell Lines

Kmail

Mansour²,

Hanaisheh³

et al. 2022

EJMP

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Background: Ficus sycomorus is one of the recommended antipsoriatic medicinal plants in the traditional Greco-Arab herbal medicine. However, the knowledge on its action mechanisms is limited. Aims: Cytotoxic, cytostatic, and anti-inflammatory effects of water/ethanolic extracts of Ficus sycomorus leaves and fruits were evaluated to test their role in the traditionally known antipsoriatic properties. Place and Duration of Study: All the experiments were done in the Department of Biology and Biotechnology, Arab American University-Palestine in 2020. Plants were collected from the Northern region of the West Bank/Palestine during the fall months in 2019 and given (Voucher code: Pharm-PCT-1030) at An-Najah National University. Methodology: MTT assay was used to evaluate cytostatic and cytotoxic effects of Ficus sycomorus extracts in human skin keratinocyte cell line (HaCaT), human monocytic cell line (THP-1)-derived macrophages, and their co-cultures. Commercial ELISA kits were applied to measure the cytokine levels. Results: Both extracts exhibited cytostatic effects with IC 50 of 656 μg/mL and 886 μg/mL for HaCat and co-culture, respectively. Leaves and fruits extracts significantly reduced dose-dependently the LPS-induced NO production by THP-1-derived macrophages from 65 μM to 19 μM and 16 μM, respectively. The fruit extracts showed higher effects than the leaf extracts and reduced the TNF-α levels from 709 pg/mL to 208 pg/mL. The fruit extracts increased the production levels of IL-10 from 74 pg/mL to 90 pg/mL. Conclusion: Ficus sycomorus extracts probably exert their antipsoriatic effects through cytostatic effects and modulation of the production levels of pro-inflammatory and anti-inflammatory cytokines.

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“…The ability of keratinocytes to resist apoptosis plays an important role in disease pathogenesis. Furthermore, keratinocytes produce inflammatory cytokines such as TNF-α, IL-23, and IL-17 together with infiltrated immune cells, which trigger the vicious cycles of the disease [42]. Preclinical pharmacology studies demonstrated that piclidenoson inhibited the proliferation of human keratinocytes (HaCat cells).…”

Section: Piclidenoson In Psoriasismentioning

confidence: 99%

Drugs Targeting the A3 Adenosine Receptor: Human Clinical Study Data

Fishman

2022

Molecules

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The A3 adenosine receptor (A3AR) is overexpressed in pathological human cells. Piclidenoson and namodenoson are A3AR agonists with high affinity and selectivity to A3AR. Both induce apoptosis of cancer and inflammatory cells via a molecular mechanism entailing deregulation of the Wnt and the NF-κB signaling pathways. Our company conducted phase I studies showing the safety of these 2 molecules. In the phase II studies in psoriasis patients, piclidenoson was safe and demonstrated efficacy manifested in significant improvements in skin lesions. Namodenoson is currently being developed to treat liver cancer, where prolonged overall survival was observed in patients with advanced liver disease and a Child–Pugh B score of 7. A pivotal phase III study in this patient population has been approved by the FDA and the EMA and is currently underway. Namodenoson is also being developed to treat non-alcoholic steatohepatitis (NASH). A Phase IIa study has been successfully concluded and showed that namodenoson has anti-inflammatory, anti-fibrosis, and anti-steatosis effects. A phase IIb study in NASH is currently enrolling patients. In conclusion, A3AR agonists are promising drug candidates in advanced stages of clinical development and demonstrate safety and efficacy in their targeted indications.

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Advances in the pathogenesis of psoriasis: from keratinocyte perspective

Cited by 270 publications

References 147 publications

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Modulatory Effects of Leave and Fruit Extracts of Ficus sycomorus on Cytostatic and Inflammatory Mediators in Monocultures and Co-cultures of Human Keratinocyte (HaCat) and Human Monocyte (THP-1) Cell Lines

Drugs Targeting the A3 Adenosine Receptor: Human Clinical Study Data

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