What's new in the treatment of atopic dermatitis?

Dattola, Annunziata; Bennardo, Luigi; Silvestri, Martina; Nisticò, Steven Paul

doi:10.1111/dth.12787

Cited by 42 publications

(33 citation statements)

References 22 publications

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“…In conclusion, our finding that the pathogenic ceramide degrading enzyme SM deacylase, discovered as a causative factor that downregulates ceramide synthesis in the SC of AD skin, is identical to the β-subunit of aCDase provides an essential and deep insight into understanding the pathogenesis of AD. This should facilitate therapeutic approaches for developing specific inhibitors of SM deacylase that could be applied topically or orally to essentially abrogate the ceramide deficiency in AD skin, which would result in the essential cure of AD even in the chronic phase, which contrasts with recent therapeutic drugs that mainly target immunological aspects in the acute phase [81].…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase, the Enzyme Involved in Its Ceramide Deficiency, Plays a Pivotal Role

Imokawa

2021

IJMS

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Atopic dermatitis (AD) is characterized clinically by severe dry skin and functionally by both a cutaneous barrier disruption and an impaired water-holding capacity in the stratum corneum (SC) even in the nonlesional skin. The combination of the disrupted barrier and water-holding functions in nonlesional skin is closely linked to the disease severity of AD, which suggests that the barrier abnormality as well as the water deficiency are elicited as a result of the induced dermatitis and subsequently trigger the recurrence of dermatitis. These functional abnormalities of the SC are mainly attributable to significantly decreased levels of total ceramides and the altered ceramide profile in the SC. Clinical studies using a synthetic pseudo-ceramide (pCer) that can function as a natural ceramide have indicated the superior clinical efficacy of pCer and, more importantly, have shown that the ceramide deficiency rather than changes in the ceramide profile in the SC of AD patients plays a central role in the pathogenesis of AD. Clinical studies of infants with AD have shown that the barrier disruption due to the ceramide deficiency is not inherent and is essentially dependent on postinflammatory events in those infants. Consistently, the recovery of trans-epidermal water loss after tape-stripping occurs at a significantly slower rate only at 1 day post-tape-stripping in AD skin compared with healthy control (HC) skin. This resembles the recovery pattern observed in Niemann–Pick disease, which is caused by an acid sphingomyelinase (aSMase) deficiency. Further, comparison of ceramide levels in the SC between before and after tape-stripping revealed that whereas ceramide levels in HC skin are significantly upregulated at 4 days post-tape-stripping, their ceramide levels remain substantially unchanged at 4 days post-tape-stripping. Taken together, the sum of these findings strongly suggests that an impaired homeostasis of a ceramide-generating process may be associated with these abnormalities. We have discovered a novel enzyme, sphingomyelin (SM) deacylase, which cleaves the N-acyl linkage of SM and glucosylceramide (GCer). The activity of SM deacylase is significantly increased in AD lesional epidermis as well as in the involved and uninvolved SC of AD skin, but not in the skin of patients with contact dermatitis or chronic eczema, compared with HC skin. SM deacylase competes with aSMase and -glucocerebrosidase (BGCase) to hydrolyze their common substrates, SM and GCer, to yield their lysoforms sphingosylphosphorylcholine (SPC) and glucosylsphingosine (GSP), respectively, instead of ceramide. Consistently, those reaction products (SPC and GSP) accumulate to a greater extent in the involved and uninvolved SC of AD skin compared with chronic eczema or contact dermatitis skin as well as HC skin. Successive chromatographies were used to purify SM deacylase to homogeneity with a single band of ≈43 kDa and with an enrichment of >14,000-fold. Analysis of a protein spot with SM deacylase activity separated by 2D-SDS-PAGE using MALDI-TOF MS/MS allowed its amino acid sequence to be determined and to identify it as the β-subunit of acid ceramidase (aCDase), an enzyme consisting of α- and β-subunits linked by amino-bonds and a single S-S bond. Western blotting of samples treated with 2-mercaptoethanol revealed that whereas recombinant human aCDase was recognized by antibodies to the α-subunit at ≈56 and ≈13 kDa and the β-subunit at ≈43 kDa, the purified SM deacylase was detectable only by the antibody to the β-subunit at ≈43 kDa. Breaking the S-S bond of recombinant human aCDase with dithiothreitol elicited the activity of SM deacylase with an apparent size of ≈40 kDa upon gel chromatography in contrast to aCDase activity with an apparent size of ≈50 kDa in untreated recombinant human aCDase. These results provide new insights into the essential role of SM deacylase as the β-subunit aCDase that causes the ceramide deficiency in AD skin.

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Section: Discussionmentioning

confidence: 99%

Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase, the Enzyme Involved in Its Ceramide Deficiency, Plays a Pivotal Role

Imokawa

2021

IJMS

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“…as weight loss in mice ( Figure S1). New treatments for AD regulate inflammatory cytokines, or are antibodies such as dupilumab [7]. In this regard, a natural compound, EA, was investigated for its effects on inflammation in AD.…”

Section: Discussionmentioning

confidence: 99%

“…The high incidence of AD causes substantial social and financial burdens on society [4]. Since the etiology of AD is complex, verified approaches to managing AD involve Janus kinase (JAK) inhibitors, corticosteroids, or regulators of the immune system such as dupilumab [5][6][7]. The critical common basis of these treatments is controlling inflammation.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effects of Ellagic Acid on Keratinocytes via MAPK and STAT Pathways

Gil

Hong

2021

IJMS

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Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by an impaired skin barrier and intense itchiness, which decreases the individual’s quality of life. No fully effective therapeutic agents have prevailed for AD due to an insufficient grasp of the complex etiology. Ellagic acid (EA), a natural compound, has anti-inflammatory properties in chronic diseases. The effects of EA on AD have not yet been explored. The present study investigated the effects of EA on TNF-α/IFN-γ-stimulated HaCaT keratinocytes and house dust mite-induced AD-like skin lesions in NC/Nga mice. Treatment with EA suppressed inflammatory responses in keratinocytes by regulating critical inflammatory signaling pathways, such as mitogen-activated protein kinases and signal transducers and activators of transcription. In vivo studies using a DfE-induced AD mouse model showed the effects of EA administration through ameliorated skin lesions via decremented histological inflammatory reactions. These results suggest that EA could be a potential therapeutic alternative for the treatment of AD by inhibiting inflammatory signaling pathways.

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“…These strategies seem to be promising options for AD. 9 However, reducing the relapse of AD remains a worldwide challenge. 10 Therefore, fuller and further understanding of the immune response mechanism of AD has important theoretical significance for the clinical diagnosis as well as the research of immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Identifying the Potential Therapeutic Targets for Atopic Dermatitis Through the Immune Infiltration Analysis and Construction of a ceRNA Network

Peng¹,

Chen²,

Yin³

et al. 2021

CCID

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Purpose This study was meant to analyze immune infiltration and construct a ceRNA network to explore the new therapeutic targets for atopic dermatitis (AD) through bioinformatics way. Patients and Methods We downloaded the AD patients’ RNA expression profile datasets (GSE63741, GSE124700) from the Gene Expression Omnibus (GEO) database, which were analyzed through the GEO2R. We explored the hub genes by the enrichment analysis and the protein–protein interaction (PPI) analysis. Moreover, we estimated immune cell types and their proportions by ImmucellAI. GSE121212 dataset validation was performed to verify the robustness of the hub genes. Then, a ceRNA network was constructed by the miRWalk, miRNet, miRDB, DIANA, TargetScan, and starbase database. Finally, gene expression analysis was performed by using RT-qPCR. Results In total, we detected 22 differentially expressed genes (DEGs), which contained 8 downregulated genes and 14 upregulated genes. There were 5 hub genes confirmed as key genes through PPI network analysis and the ROC curves. KEGG pathway analysis revealed that they were significantly enriched in the IL-17 signaling pathway and GO analysis showed mainly in the immune cell chemotaxis. The immune infiltration profiles were different between normal controls and AD, and each of the key genes (S100A7, S100A8, S100A9, and LCE3D) was significantly correlated with the main infiltration cell of AD. A lncRNA–miRNA–mRNA ceRNA network containing the key genes was constructed, and NEAT1 and XIST, the core of ceRNA network, were significantly overexpressing verified by RT-qPCR in AD patients. Conclusion Altogether, the key genes and their ceRNA network provided a novel perspective to the immunomodulation of AD, which may be potential and new therapeutic targets for AD.

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What's new in the treatment of atopic dermatitis?

Cited by 42 publications

References 22 publications

Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase, the Enzyme Involved in Its Ceramide Deficiency, Plays a Pivotal Role

Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase, the Enzyme Involved in Its Ceramide Deficiency, Plays a Pivotal Role

Anti-Inflammatory Effects of Ellagic Acid on Keratinocytes via MAPK and STAT Pathways

Identifying the Potential Therapeutic Targets for Atopic Dermatitis Through the Immune Infiltration Analysis and Construction of a ceRNA Network

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