Downregulation of Cathepsin B Reduces Proliferation and Inflammatory Response and Facilitates Differentiation in Human HaCaT Keratinocytes, Ameliorating IL-17A and SAA-Induced Psoriasis-Like Lesion

Xu, Di; Wang, Jie

doi:10.1007/s10753-021-01477-0

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…Next, 10 μ l of CCK-8 (Vazyme, Nanjing, China) reagent was added to each well at the indicated time points (0, 24, 48, and 72 h) and cultured for another 2 hr according to the manufacturer's instructions. The absorbance value was measured at 460 nm using a microplate reader (Bio-Rad, Hercules, CA, USA) [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

miR-124-3p Delivered Using Exosomes Attenuates the Keratinocyte Response to IL-17A Stimulation in Psoriasis

Liu

Ju²

2022

Oxidative Medicine and Cellular Longevity

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Background and Objective. To explore the effect of miR-124-3p delivered by exosomes on psoriatic keratinocytes stimulated by IL-17A. Methods. NHEKs, HaCaT cells, and HEK 293T cells were treated with IL-17A. CCK-8 assays were performed to detect cell activity, and immunofluorescence staining and Western blotting were performed to detect the protein expression of STAT3. After isolation of exosomes via ultracentrifugation, the contents of miR-124-3p and oxidative stress markers such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in keratinocytes were measured. Subsequently, transcriptomic analysis was performed using RNA-seq. Data were analysed by using the “edgeR” package within R. After verifying the abnormally expressed genes stimulated by IL-17A, a dual luciferase reporter assay was used to determine the interaction between miR-124-3p and STAT3. Finally, BALB/c mice were used to establish a psoriasis model for analysis. The effect of elevated miR-124-3p on the psoriasis mouse model was determined by exosomal delivery of miR-124-3p. Results. IL-17 intervention enhanced the cell activity of keratinocytes ( P < 0.05 ). miR-124-3p was identified by RNA-seq as one of the differentially expressed miRNAs stimulated by IL-17A. miR-124-3p overexpression induced decreased STAT3 and MDA levels, increased SOD and GSH-Px levels in keratinocytes, and alleviated emergency responses of sclerosis damage ( P < 0.05 ). The dual luciferase reporter assay results confirmed that STAT3 was regulated by miR-124-3p in a targeted manner ( P < 0.05 ). Finally, miR-124-3p delivered by exosomes effectively alleviated the pathological manifestations and oxidative stress responses of psoriatic mice. Conclusions. miR-124-3p regulates keratinocyte activity via STAT3 in response to IL-17A stimulation. The ectopic expression of miR-124-3p in psoriatic skin reduces IL-17A-induced inflammation and inhibits the STAT3 pathway, thus alleviating the symptoms of psoriasis. The findings of this study suggest that exosomes can be used to therapeutically deliver miR-124-3p to keratinocytes and psoriatic lesions, which may provide novel insight for psoriasis treatment.

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Section: Methodsmentioning

confidence: 99%

miR-124-3p Delivered Using Exosomes Attenuates the Keratinocyte Response to IL-17A Stimulation in Psoriasis

Liu

Ju²

2022

Oxidative Medicine and Cellular Longevity

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“…CTSB was the only gene to be significantly upregulated in MCs as well, suggesting that Cathepsin B could serve as common indicator of MC-dependent itch signature in psoriasis. Cathepsin B is upregulated in animal models of inflamed skin, where it contributes to aberrant keratinocyte proliferation [90,91]. We demonstrated in vitro that cathepsin B is released by human peripheral blood-derived MCs in response to stimulation by neuropeptide SP (Figure 7c).…”

Section: Cathepsin B Is a Predictive Indicator Of Mast Cell-dependent...mentioning

confidence: 77%

Human Mast Cells Upregulate Cathepsin B, a Novel Marker of Itch in Psoriasis

West,

Tontini,

Atmoko

et al. 2023

Cells

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Mast cells (MCs) contribute to skin inflammation. In psoriasis, the activation of cutaneous neuroimmune networks commonly leads to itch. To dissect the unique contribution of MCs to the cutaneous neuroinflammatory response in psoriasis, we examined their density, distribution, relation to nerve fibres and disease severity, and molecular signature by comparing RNA-seq analysis of MCs isolated from the skin of psoriasis patients and healthy volunteers. In involved psoriasis skin, MCs and Calcitonin Gene-Related Peptide (CGRP)-positive nerve fibres were spatially associated, and the increase of both MC and nerve fibre density correlated with disease severity. Gene set enrichment analysis of differentially expressed genes in involved psoriasis skin showed significant representation of neuron-related pathways (i.e., regulation of neuron projection along with dendrite and dendritic spine morphogenesis), indicating MC engagement in neuronal development and supporting the evidence of close MC–nerve fibre interaction. Furthermore, the analysis of 208 identified itch-associated genes revealed that CTSB, TLR4, and TACR1 were upregulated in MCs in involved skin. In both whole-skin published datasets and isolated MCs, CTSB was found to be a reliable indicator of the psoriasis condition. Furthermore, cathepsin B+ cells were increased in psoriasis skin and cathepsin B+ MC density correlated with disease severity. Therefore, our study provides evidence that cathepsin B could serve as a common indicator of the MC-dependent itch signature in psoriasis.

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“… [ 41 , 42 ] S1P Keratinocytes S1P lyase is a modulating factor for proliferation and differentiation, and support its potential as a therapeutic target for psoriasis in human keratinocytes. [ 43 ] Cathepsin B Keratinocytes Cathepsin B might be a promising therapeutic target for psoriasis-like lesion, which helps to develop an anti-psoriatic agent [ 44 ] Gasdermin D Keratinocytes Targeted focal death could be considered a therapeutic strategy for psoriasis [ 48 ] AQP1 Endothelial cells The present study confirms that AQP1 is a pro-angiogenic protein and therefore may be a candidate target for anti-angiogenic molecules [ 49 ] HIF-1α Keratinocytes May provide insights into the pathophysiology of neuro inflammatory skin diseases such as psoriasis [ 50 ] EDIL3 αvβ3- FAK/MEK/ERK Endothelial cells EDIL3 and αvβ3- FAK/MEK/ERK signaling pathways will provide valuable therapeutic targets for controlling angiogenesis [ 53 ] TSG-6 Neutrophils Blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis. [ 54 , 69 ] USP15 Keratinocytes USP15 may be a potential target for the treatment of psoriasis [ 56–58 ] NFKBIZ ...…”

Section: Discussionmentioning

confidence: 99%

“… 41 , 42 Silencing Cathepsin B ( CTSB ) rescues both the excessive proliferation and inflammatory responses induced by IL-17A and Serum Amyloid A ( SAA ), and corrects the deficiency in normal differentiation. 43 Exogenous CK2 promotes excessive proliferation and abnormal differentiation in human keratinocytes, which can be reversed by siRNA-mediated CK2 inhibition. CK2 downregulation reduces IL-17A expression and eliminates both proliferation and inflammatory cytokine expression in keratinocytes induced by IL-17A .…”

Section: Targeting Keratinocytesmentioning

confidence: 99%

Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments

Zhao,

Wei

et al. 2024

ITT

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Psoriasis is a chronic inflammatory skin disease characterized by the excessive proliferation of keratinocytes and heightened immune activation. Targeting pathogenic genes through small interfering RNA (siRNA) therapy represents a promising strategy for the treatment of psoriasis. This mini-review provides a comprehensive summary of siRNA research targeting the pathogenesis of psoriasis, covering aspects such as keratinocyte function, inflammatory cell roles, preclinical animal studies, and siRNA delivery mechanisms. It details recent advancements in RNA interference that modulate key factors including keratinocyte proliferation (Fibroblast Growth Factor Receptor 2, FGFR2 ), apoptosis (Interferon Alpha Inducible Protein 6, G1P3 ), differentiation (Grainyhead Like Transcription Factor 2, GRHL2 ), and angiogenesis (Vascular Endothelial Growth Factor, VEGF ); immune cell infiltration and inflammation (Tumor Necrosis Factor-Alpha, TNF-α ; Interleukin-17, IL-17 ); and signaling pathways ( JAK-STAT , Nuclear Factor Kappa B, NF-κB ) that govern immunopathology. Despite significant advances in siRNA-targeted treatments for psoriasis, several challenges persist. Continued scientific developments promise the creation of more effective and safer siRNA medications, potentially enhancing the quality of life for psoriasis patients and revolutionizing treatments for other diseases. This article focuses on the most recent research advancements in targeting the pathogenesis of psoriasis with siRNA and explores its future therapeutic prospects.

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Downregulation of Cathepsin B Reduces Proliferation and Inflammatory Response and Facilitates Differentiation in Human HaCaT Keratinocytes, Ameliorating IL-17A and SAA-Induced Psoriasis-Like Lesion

Cited by 7 publications

References 27 publications

miR-124-3p Delivered Using Exosomes Attenuates the Keratinocyte Response to IL-17A Stimulation in Psoriasis

miR-124-3p Delivered Using Exosomes Attenuates the Keratinocyte Response to IL-17A Stimulation in Psoriasis

Human Mast Cells Upregulate Cathepsin B, a Novel Marker of Itch in Psoriasis

Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments

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