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Transcriptomic analysis of low-density neutrophils (LDNs) in acute generalized pustular psoriasis (GPP)

ABSTRACT: Transcriptomic analysis of low-density neutrophils (LDNs) in acute generalized pustular psoriasis (GPP)

PROVIDER: PRJNA826891 | ENA |

REPOSITORIES: ENA

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Transcriptomic analysis of low-density neutrophils (LDNs) in acute generalized pustular psoriasis (GPP)

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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A distinct immature low-density neutrophil population characterizes acute generalized pustular psoriasis [PBMC]

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Mature interleukin-36γ induces stratum corneum exfoliation in generalized pustular psoriasis by suppressing corneodesmosin

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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Comparison of healthy, plaque psoriasis and pustular psoriasis FFPE skin biopsies

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.

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A distinct immature low-density neutrophil population characterizes acute generalized pustular psoriasis [PBMC]

Project description:A distinct immature low-density neutrophil population characterizes acute generalized pustular psoriasis [PBMC]

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Neutrophils RNAseq from Generalised Pustular Psoriasis patients and healthy individuals

Project description:Neutrophils RNAseq from Generalised Pustular Psoriasis patients and healthy individuals

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Mature interleukin-36γ induces stratum corneum exfoliation in generalized pustular psoriasis by suppressing corneodesmosin

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Pathophysiology of Generalized Pustular Psoriasis.

Project description:Generalized pustular psoriasis (GPP) is a rare, severe form of pustular psoriasis characterized by widespread, recurrent episodes of neutrophil-rich pustule formation in the epidermis, which can be accompanied by fever and systemic inflammation. Recent clinical, histologic, and genetic evidence indicates that GPP is a distinct entity from plaque psoriasis, with different cytokine pathways predominant in the manifestation of each disease. The interleukin-36 (IL-36) signaling cascade plays a key role in regulating the innate immune system, and its dysregulation appears central to the pathogenesis of GPP. The altered expression of various IL-36 pathway constituents has been shown to cause a positive feedback loop of uncontrolled signaling and excess production of inflammatory cytokines, which in turn leads to chemokine induction and neutrophil recruitment in the epidermis. Given the potentially life-threatening nature of GPP episodes, drug interventions that rapidly achieve disease resolution are required. Early phase data indicate that treatments targeting various components of the IL-36 inflammatory cascade represent promising areas of research. However, there are currently no therapeutic agents specifically approved for GPP in the USA or Europe. Understanding the inflammatory pathways, associated risk factors, and role of neutrophils in the manifestation and perpetuation of GPP flares remains a key goal in developing effective therapeutics. In this article, we summarize the current understanding of GPP, describe novel therapeutic opportunities, and detail how the unique pathophysiology of the disease may inform future treatment strategies.

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Project description:pre- and post spesolimab treatment gene expression analysis of blood as well as skin biopsy samples.

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