IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis
Andrew Johnston,Xianying Xing,Liza Wolterink,Drew H. Barnes,Z. Yin,Z. Yin,Laura J. Reingold,J. Michelle Kahlenberg,Paul W. Harms,Johann E. Gudjonsson +9 more
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TLDR
Sustained activation of IL‐1 and IL‐36 in GPP is indicated, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL‐36 inflammatory axis is a potent driver of disease pathology in G PP.Abstract:
Background 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 and warrant a better understanding of GPP pathogenesis. Objective We sought to understand better the disease mechanism of GPP to allow improved targeted therapies. Methods We performed a gene expression study on formalin-fixed paraffin-embedded GPP (n = 28) and PV (n = 12) lesional biopsies and healthy control (n = 20) skin. Differential gene expression was analyzed using gene ontology and enrichment analysis. Gene expression was validated with quantitative RT-PCR and immunohistochemistry, and a potential disease mechanism was investigated using primary human cell culture. Results Compared with healthy skin, GPP lesions yielded 479 and PV 854 differentially expressed genes, respectively, with 184 upregulated in both diseases. We detected significant contributions of IL-17A, TNF, IL-1, IL-36, and interferons in both diseases; although GPP lesions furnished higher IL-1 and IL-36 and lower IL-17A and IFN-γ mRNA expression than PV lesions did. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules, and we show that both neutrophils and neutrophil proteases activate IL-36. Suggesting another mechanism regulating IL-36 activity, the protease inhibitors serpin A1 and A3, which inhibit elastase and cathepsin G, respectively, were upregulated in both diseases and inhibited activation of IL-36. Conclusions Our data indicate sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP.read more
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Psoriasis Pathogenesis and Treatment.
Adriana Rendon,Knut Schäkel +1 more
TL;DR: The role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis is described, which includes a comprehensive review of well-established widely available therapies and novel targeted drugs.
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Mechanisms and applications of the anti-inflammatory effects of photobiomodulation.
TL;DR: One of the most reproducible effects of PBM is an overall reduction in inflammation, which is particularly important for disorders of the joints, traumatic injuries, lung disorders, and in the brain.
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Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation
Seitaro Nakagawa,Masanori Matsumoto,Yuki Katayama,Rena Oguma,Seiichiro Wakabayashi,Tyler Nygaard,Shinobu Saijo,Naohiro Inohara,Michael Otto,Hiroyuki Matsue,Gabriel Núñez,Yuumi Nakamura +11 more
TL;DR: Using a murine epicutaneous infection model, S. aureus-expressed phenol-soluble modulin (PSM)α, a group of secreted virulence peptides, is required to trigger cutaneous inflammation in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88.
Journal ArticleDOI
Staphylococcus aureus Epicutaneous Exposure Drives Skin Inflammation via IL-36-Mediated T Cell Responses.
Haiyun Liu,Nathan K. Archer,Carly A. Dillen,Yu Wang,Alyssa G. Ashbaugh,Roger V. Ortines,Tracy Kao,S. Lee,Shuting S. Cai,Robert J. Miller,Mark C. Marchitto,Emily Zhang,Daniel P. Riggins,Roger D. Plaut,Scott Stibitz,Raif S. Geha,Lloyd S. Miller +16 more
TL;DR: A previously unknown pathway by which S. aureus epicutaneous exposure to mouse skin promoted MyD88-dependent skin inflammation initiated by IL-36, but not IL-1α/β, IL-18, or IL-33 is defined.
References
More filters
Journal ArticleDOI
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
Aravind Subramanian,Pablo Tamayo,Vamsi K. Mootha,Sayan Mukherjee,Benjamin L. Ebert,Michael A. Gillette,Amanda G. Paulovich,Scott L. Pomeroy,Todd R. Golub,Eric S. Lander,Jill P. Mesirov +10 more
TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
Journal ArticleDOI
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Rafael A. Irizarry,Bridget G. Hobbs,Francois Collin,Yasmin Beazer-Barclay,Kristen J. Antonellis,Uwe Scherf,Terence P. Speed +6 more
TL;DR: There is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities, and the exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values.
Journal ArticleDOI
Adjusting batch effects in microarray expression data using empirical Bayes methods
TL;DR: This paper proposed parametric and non-parametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples.
Journal ArticleDOI
ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks
Gabriela-Luana Bindea,Bernhard Mlecnik,Hubert Hackl,Pornpimol Charoentong,Marie Tosolini,Amos Kirilovsky,Wolf H. Fridman,Franck Pagès,Zlatko Trajanoski,Jérôme Galon +9 more
TL;DR: ClueGO is an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes and creates a functionally organized GO/pathway term network.
Journal ArticleDOI
TM4: a free, open-source system for microarray data management and analysis.
Alexander I. Saeed,Vasily Sharov,James R. White,J. Li,Wei Liang,Nirmal Bhagabati,John C. Braisted,Maria I. Klapa,T. Currier,Mathangi Thiagarajan,Alexander Sturn,Mark Snuffin,A. Rezantsev,D. Popov,A. Ryltsov,E. Kostukovich,I. Borisovsky,Z. Liu,A. Vinsavich,V. Trush,John Quackenbush +20 more
TL;DR: This research presents a novel and scalable approach to genome engineering that addresses the challenge of integrating RNAseq data to provide real-time information about the “silent” response of the immune system to DNA editing.
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