IL-4/IL-13 Inhibitors for Atopic Dermatitis Induce Psoriatic Rash Transcriptionally Close to Pustular Psoriasis
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ABSTRACT:
PROVIDER: PRJNA770682 | ENA |
REPOSITORIES: ENA
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Project description:Loss-of-function mutations in the IL36RN gene encoding IL-36 receptor antagonist (IL-36RA) cause familial generalized pustular psoriasis (GPP), which sometimes begins shortly after birth and is difficult to treat, and its effects on the epidermis are unclear. This study aimed to investigate the involvement of IL-36 receptor agonists in the epidermal formation of GPP. In this study, we found that IL-36 receptor agonists, especially mature IL-36γ, stimulate IL-8 and proIL-36γ production in the epidermis, while down-regulating the genes encoding epidermal cornified envelope-related proteins such as corneodesmosin. IL-36 receptor antagonists and monoclonal anti-IL-36γ antibodies counteract the effect of mature IL-36γ on corneodesmosin in keratinocytes in a dose-dependent manner. In the epidermis of generalized pustular psoriasis patients with IL36RN loss-of-function mutations, proIL-36γ is overproduced in the epidermis and corneodesmosin protein expression is markedly decreased in the region of giant subcorneal pustules called Kogoj’s spongiform pustules with high neutrophil infiltration. IL-8 induced by mature IL-36γ induces several neutrophils in the epidermis, and the newly produced proIL-36γ is cleaved to the mature form by neutrophil proteases. This newly produced mature IL-36γ was predicted to further suppress the gene expression of the granulosa-stratum-associated protein, corneodesmosin, leading to significant stratum corneum exfoliation and formation of giant subcorneal pustules. Overall, our results elucidate the mechanism underlying the formation of Kogoj’s spongiform pustules in generalized pustular psoriasis.
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Project description:Psoriasis is a chronic inflammatory disease of the skin for which no cure has emerged. Its complex etiology requires the development of an in vitro model that appropriately recapitulates the physiopathology of this disease. In this study, we exploited the self-assembly method in order to develop a new tissue-engineered model of psoriatic skin substitutes. To circumvent the addition of immune cells, we supplemented the reconstructed psoriatic substitutes with a cocktail of four cytokines, TNF-α, IL-1α, IL-6 and IL-17, and monitored their impact on global gene expression by DNA microarray. The cytokines-supplemented substitutes have a more irregular epidermis, with protuberances and much thinner areas. Most interestingly, gene profiling on microarrays identified several genes reported as being deregulated psoriasis skin in vivo. Indeed, expression of the S100A12, IL8, DEFB4A and KYNU genes increased dramatically compared to their level in normal skin substitutes (P <0.005 to <0.05). In addition, the ACSBG1 gene, reported to be repressed in psoriasis, was also repressed in the cytokines-supplemented psoriatic substitutes compared to the controls (P <0.005). The product encoded by the genes deregulated in the cytokines-supplemented substitutes belong to biological pathways, such as the inflammatory and the immune responses, that are similarly altered in psoriasis in vivo. In conclusion, addition of cytokines to involved psoriatic substitutes alters the transcriptome of these cells in a manner similar to that observed with psoriasis in vivo. The addition of this pro-inflammatory cocktail, comparable cytokine in vivo psoriasis, prepares us for the next step: the characterization of the model once added immune cells. Tissue-engineered psoriatic human skin (TEPHS) cultivated with (number of replicates: 3) or without (number of replicates: 3) Cytokines (IL-17a, IL-6, IL1a, TNF-a).
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Project description:Generalized pustular psoriasis (GPP) is a severe disease featured by neutrophilic pustules and enhanced IL-36 inflammatory pathway in skin. Recently, a transcriptomic analysis of PBMCs and neutrophils in MPO-deficient GPP patients has been performed in stable disease state. However, transcriptomic profiling of PBMCs during acute flare of GPP is unclear. Here, we reported a predominant neutrophil signature in GPP PBMC and a marked increase in the CD66+CD16+ low-density neutrophils (LDNs) within the PBMC fraction of acute GPP patients. Transcriptomic and functional analysis of LDNs revealed a hypoinflammatory phenotype yet enhanced release of neutrophil granule proteases, implicating that LDNs might contribute to the IL-36-mediated inflammation in GPP patients.
2022-04-20 | GSE200977 | GEO
Project description:Generalized pustular psoriasis (GPP) is a severe disease featured by neutrophilic pustules and enhanced IL-36 inflammatory pathway in skin. Recently, a transcriptomic analysis of PBMCs and neutrophils in MPO-deficient GPP patients has been performed in stable disease state. However, transcriptomic profiling of PBMCs during acute flare of GPP is unclear. Here, we reported a predominant neutrophil signature in GPP PBMC and a marked increase in the CD66+CD16+ low-density neutrophils (LDNs) within the PBMC fraction of acute GPP patients. Transcriptomic and functional analysis of LDNs revealed a hypoinflammatory phenotype yet enhanced release of neutrophil granule proteases, implicating that LDNs might contribute to the IL-36-mediated inflammation in GPP patients.
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Project description:Vitamin D3 and deconvoluting a rash
| PRJNA905668 | ENA
Project description:Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory thus a better understanding the pathogenesis of GPP is warranted. To assess the pathophysiological differences between GPP and PV we performed a gene expression study on formalin-fixed paraffin-embedded biopsies of GPP (n=30) and PV (n=12) lesions and healthy control (n=20) skin. Compared with healthy skin, GPP lesions yielded 365 and PV 898 differentially expressed genes respectively, with 190 upregulated in both diseases. We detected higher expression of IL-1 and IL-36 cytokines in GPP lesions compared with PV, and this occurred proximal to neutrophils. We show both activated neutrophils and isolated neutrophil proteases can activate IL-36. Diverging from the Th1/Th17 pathophysiology of PV, significantly fewer IL23A, IL17A, IFNG, CXCL9, CXCL10 and MX1 transcripts were detected in GPP lesions. Our data indicate a level of sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration and pustule formation, suggesting that the IL-1 and IL-36 inflammatory axes are the main drivers of disease pathology in GPP.
2017-01-27 | GSE79704 | GEO