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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200836 | GEO | 2022/04/18

REPOSITORIES: GEO

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

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

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.

2023-11-09 | GSE235635 | GEO

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.

2017-01-27 | GSE79704 | GEO

Neutrophil extracellular trap induction by alcohol generates unique low-density neutrophils with defective functions and impaired clearance contributing to liver damage in alcoholic hepatitis

Project description:Alcoholic hepatitis (AH) is characterized by severe liver and systemic inflammation and high mortality. Although numerous studies correlated neutrophil counts with poor clinical outcomes, the role of neutrophils in AH is poorly understood. Here, we report that neutrophils contribute to liver damage through increased neutrophils extracellular traps (NET) production in AH patients and mouse models with a concordant significant increase of low-density neutrophils (LDNs) in AH patients. Transcriptome analysis revealed that high-density neutrophils (HDNs) are activated and more prone to release NET, whereas LDNs exhibit exhausted phenotype. We show that alcohol-induced NET release in HDNs induces a unique LDN subset with decreased functionality and reduced clearance. Elimination of both defective HDNs and LDNs through in vivo neutrophil depletion or prevention of NET production with granulocyte colony stimulating factor (G-CSF) treatment ameliorate alcohol-induced liver damage. Our findings uncover alcohol-induced neutrophil phenotypic changes and provide mechanistic insights for therapeutic interventions in AH.

2023-04-08 | GSE171809 | GEO

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

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

| PRJNA826891 | ENA

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice

Project description:Diabetes is associated with an increase in neutrophil NET production. Low density neutrophils (LDNs) have a greater propensity for spontaneous production of NETs, and are increased in the diabetic host during infection with S. aureus. We compared gene expression between high density (HDN) and LDNs isolated from the blood of infected db/db mice.

2019-04-08 | GSE122195 | GEO

Childhood Onset Rheumatic Disease Gene Expression Profile

Project description:Total RNA from peripheral blood mononuclear cells (PBMC) and neutrophils from children with juvenile dermatomyositis (JDM) and juvenile idiopathic arthritis (JIA) were separately compared to pediatric control samples. Keywords: pediatric rheumatic disease, blood, PBMC, neutrophil, JIA, JDM JIA PBMC n = 14 JIA neutrophils n=14 JDM PBMC n = 13 JDM neutrophils n = 14 pediatric control PBMC n = 15 pediatric control neutrophils n = 13

2009-03-25 | E-GEOD-11083 | biostudies-arrayexpress

Bulk RNA-Seq of human neutrophils and monocytes isolated from healthy controls, G-CSF-treated donors, HSCT, PDAC and IPMN patients

Project description:We aimed to characterize transcriptome plasticity of human myeloid cells in response to stress induced myelopoiesis. We performed bulk RNA sequencing (RNA-Seq) analyses of normal density neutrophils (NDNs), low density neutrophils (LDNs), and monocytes isolated from the peripheral blood (PB) of healthy controls (n=19), of G-CSF-treated donors (n=17) as well as of patients receiving hematopoietic stem cell transplantation (HSC-T; n=8), patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC; n=15) or intraductal papillary mucinous neoplasms (IPMN; n=14). We also analyzed neutrophil differentiation intermediates from bone marrow samples of controls (n=3) or HSC-T patients (n=7). We generated a total of 210 RNA-Seq samples from 73 individuals.

2022-11-29 | E-MTAB-11190 | biostudies-arrayexpress

S. aureus drives expansion of low density neutrophils in the diabetic host

Project description:Abstract S. aureus is a major opportunistic pathogen infecting patients with diabetes. Increased mortality was observed following IV S. aureus infection in diabetic mice compared to non-diabetic controls, correlating with increased numbers of low density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDN development is dependent on TGFβ, which was more activated in the diabetic host. Neutralization of TGFβ, or the integrin responsible for its activation α5β8, reduced numbers of LDNs and improved survival. Comparison of high and low density neutrophils identified PTEN signaling as a central regulator of LDN NET release. Inhibition of PTEN improved survival and decreased NET production in infected diabetic mice. MEDI4893*, a monoclonal antibody that neutralizes alpha toxin (AT) in development for prevention of S. aureus infection, was able to block TGFβ activation, reduce LDNs and NETs, and significantly improve survival. Our data identify a population of neutrophils in infected diabetic mice which correlated with decreased survival and increased NET production. Targeting a single virulence factor of S. aureus prevented emergence of the LDN population and improved survival, supporting potential use of pathogen specific antibodies for treating diabetic infections.

2019-04-26 | PXD012176 | Pride

Childhood Onset Rheumatic Disease Gene Expression Profile

2009-03-25 | GSE11083 | GEO

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