Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE192832 | GEO | 2022/03/06
REPOSITORIES: GEO
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Project description:Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI. NS patients suffer from a severe skin barrier defect, display inflammatory skin lesions and superficial scaling with atopic manifestations. They can present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). Here we employed a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells and allergic phenotypes of NS-ILC and NS-SE patients. This integrated multi-omic approach revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesional skin and blood in both NS endotypes. While the molecular profiles of NS-ILC and NS-SE lesional skin were very similar, non-lesional skin of each disease subtype displayed distinctive molecular features. NS-SE non-lesional and lesional epidermis showed activation of the type I IFN signaling pathway, which is involved in skin homeostasis and inflammation. NS-ILC lesional skin differed from NS-ILC non-lesional skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a Th2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a Th9 axis with increased CCL22/MDC and CCL17/TARC serum levels. This study identifies IL-17/IL-36 as predominant signaling axes in both NS endotypes and unveils distinct molecular features characterizing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
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Project description:Ichthyosis molecular fingerprinting shows profound Th17-skewing and a unique barrier genomic signature
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Project description:Autosomal recessive congenital ichthyosis (ARCI) is a group of rare inherited skin disorders characterized by remarkable hyperkeratosis. Transglutaminase 1 (TGM1) mutations have been reported to be involved in four different phenotypes of ARCI, including lamellar ichthyosis (LI), non-bullous congenital ichthyosiform erythroderma (NBCIE), bathing suit ichthyosis (BSI), and self-improving collodion ichthyosis (SICI) according to the clinical presentation and histopathology. TGM1 has been found as a defective gene in a large amount of patients with LI and some patients with NBCIE, BSI and SICI. To further understand the effect of TGM1 mutations in epidermal cells development, we performed the transcriptome analysis of HEK293T and HaCaT cells transfected with TGM1 shRNA, TGM1 wild-type and mutant clones. The transcriptomic analysis revealed the effects of TGM1 on cell-cell interaction by suppressing genes involved in the gap junctions, tight junctions and desmosomes. These findings suggested that the TGM1 deficiency disturbed the balance of keratinocytes proliferation and differentiation processes and impaired the epithelial barrier function. The results provided the basis for further understanding on the etiology of ARCI. To explore the functional impacts on some of the TGM1mutations identified, we cloned and transfected the TGM1 wild type and mutant clones into HEK293T and HaCaT cells. R142C and R348X sequence mutations observed in ARCI (Autosomal recessive congenital ichthyosis) patients were generated. The shRNA targeting TGM1 and a scrambled negative control were obtained from Invitrogen (Carlsbad, CA). The293T and HaCaT cells were transfected with over-expression clones carry either wild-type or mutated TGM1sequence. Cells were harvested 48 hours post-transfection.
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Project description:Autosomal recessive congenital ichthyoses (ARCI) are a group of non-syndromic congenital keratinization disorders including harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma with a total prevalence of 1:200,000. Affected individuals who are often born as collodion babies present with generalized scaling of the skin. This reflects a physical compensation for the defective cutaneous permeability barrier underlying all ichthyoses. Inactivity of 12R-lipoxygenase (12R-LOX) is a frequent cause of ARCI. Epidermis-specific conditional knockout of Alox12b encoding 12R-LOX was established in mice using the Cre-Lox system. Tamoxifen-induced Alox12b inactivation in mouse skin caused an ichthyosis-like phenotype. We used microarray to compare the gene expression profile in the epidermis of mice after tamoxifen induced Alox12b inactivation with that of control animals. Inactivation of Alox12b was associated with the upregulation of genes involved in keratinization, cholesterol biosynthesis, and Fc-epsilon receptor signaling.
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Project description:Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in the gene SPINK5 encoding the protease inhibitor LEKTI. NS patients suffer from a severe skin barrier defect, display inflammatory skin lesions and superficial scaling with atopic manifestations. They can present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). Here we employed a combination of several molecular profiling methods to comprehensively characterize the skin, immune cell and allergic phenotypes of NS-ILC and NS-SE patients. This integrated multi-omic approach revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesional skin and blood in both NS endotypes. While the molecular profiles of NS-ILC and NS-SE lesional skin were very similar, non-lesional skin of each disease endotype displayed distinctive molecular features. NS-SE non-lesional and lesional epidermis showed activation of the type I IFN signaling pathway, which is involved in skin homeostasis and inflammation. NS-ILC lesional skin differed from NS-ILC non-lesional skin by upregulated complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a Th2-driven allergic response in NS-ILC, whereasNS-SE patients displayed mainly a Th9 axis with increased CCL22/MDC and CCL17/TARC serum levels. This study identifies IL-17/IL-36 as predominant signaling axes in both NS endotypes and unveils distinct molecular features characterizing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
Proteins were extracted from frozen skin samples using RapiGest containing buffer followed by reduction and alkylation using 5 mM Dithiothreitol and 15 mM Iodoacetamide. Proteins were digested by first incubating with LysC followed by incubating with Trypsin. A masterpool containing 10 microgram of desalted peptides (PreOmics) from each sample was fractionated (Agilent 1100 HPLC system). Fractions were measured using data dependent acquisition (DDA) on a Q-Exactive Plus (Thermo Scientific, San Jose, CA) mass spectrometer. For the proteomic comparison 1 microgram of peptide from each patient was measured in data independent acquisition (DIA) mode using the same gradient and instrument as for the masterpool fractions.
The resulting .raw files for both the fractionated masterpool (16 DDA files) as well as the patient cohort measurements (33 DIA files) are uploaded here. Additionally, the converted mzML files and annotation files are provided. The complete data analysis of the library generation and the DIA data analysis is uploaded as compressed galaxy history files which can be downloaded, extracted and imported on https://usegalaxy.eu.
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