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Atopic Dermatitis
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Luz Fonacier, Amanda Schneider
Atopic dermatitis has a pathogenesis of complex immune dysregulation and interplay of genetic, environmental, epidermal and psychological factors. The stratum corneum of healthy skin functions as a barrier and provides water-retaining properties. It contains an extracellular lipid matrix including ceramides, cholesterol and free fatty acids (Leung 2001). When this layer becomes dry and fissured, it becomes a portal of entry for bacteria, mostly commonly Staphylococcus aureus. Disruption of the integrity of the stratum corneum exposes epidermal and dermal extracellular matrix proteins, such as fibronectin and collagen which can serve as anchors for S. aureus binding via adhesions (Cho et al. 2001). In AD, the stratum corneum lipid composition contains decreased levels of ceramides and sphingosine which normally act as water-retaining molecules. Deficient ceramide increases secretion of ceramidases, which leads to increased transepidermal water loss, resulting in dry, cracked skin of AD (Cardona et al. 2006, Arikawa et al. 2002). Sphingosine has been shown to normally possess antimicrobial properties, thus deficiencies may favor bacterial colonization (Arikawa et al. 2002).
Pathophysiology of Atopic Dermatitis and Atopiform Dermatitis
Published in Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld, Atopic Dermatitis and Eczematous Disorders, 2014
Stratum corneum ceramide levels are determined by the balance of enzymes that favor its production, ie, sphingomyelinase and β-glucocerebrocidase, and those that cause its degradation, eg, ceramidase. Reduced ceramide in AD may be caused by abnormally high expression of the enzyme, sphingomyelin (SM) deacylase, and decreased epidermal acid sphingomyelinase (SMase) activity (Hara et al. 2000, Jensen et al. 2004), eg, the stratum corneum from AD-lesional volar forearm skin expresses sphingomyelin deacylase at levels 5–17 times higher than normal skin and that of nonlesional skin of AD patients expresses levels 3–9 times higher. SM deacylase hydrolyzes sphingomyelin to produce sphingosophosphorylcholine (SPC) instead of ceramide normally formed by sphingomyelinase. In fact, levels of stratum corneum SPC have been shown to be upregulated in both involved and uninvolved AD skin (Okamoto et al. 2003). As SPC is a potent inducer of intercellular adhesion molecule-1 (ICAM-1) expression by keratinocytes, induces mast cell degranulaton and histamine release, and has a direct effect on nerves, it has been suggested that it may play an important role in AD epidermal inflammation and itching responses (Imokawa et al. 1999, Andoh et al. 2009, Kim et al. 2010). SPC also stimulates keratinocyte transglutaminase activity and cornified envelope formation, so it may alter the keratinization process in AD (Higuchi et al. 2001). Finally, SPC significantly decreases filaggrin gene transcription, implying that it plays a pivotal role in impairment of the epidermal permeability barrier in AD lesional skin (Choi et al. 2010).
High-throughput discovery of novel small-molecule inhibitors of acid Ceramidase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mazen Aseeri, José Luis Abad, Antonio Delgado, Gemma Fabriàs, Gemma Triola, Josefina Casas
Ceramide can be generated de novo from serine and palmitate, by the degradation of sphingomyelin catalysed by sphingomyelinases and by the acylation of sphingosine in the salvage pathway. Ceramide degradation is in turn mediated by the actions of different ceramidases that are distinguished by the pH required for optimal activity, i.e. acid ceramidase (AC, ASAH1), neutral ceramidase (NC, ASAH2) and alkaline ceramidases 1, 2 and 3 (ACER1, ACER2 and ACER3)9. Different functions and cellular roles, probably defined by their intracellular localisation and substrate specificity, have been suggested for these ceramidases. Hence, NC overexpression has been related to colon carcinogenesis10, whereas ACER3 has been reported to contribute to hepatocellular carcinoma11 and to acute myeloid leukaemia pathogenesis12.
AdipoRs- a potential therapeutic target for fibrotic disorders
Published in Expert Opinion on Therapeutic Targets, 2019
Lingman Ma, Xuanyi Li, Zhaoshi Bai, Xinhao Lin, Kejiang Lin
Despite the traditional AMPK pathway, APN also exhibits anti-inflammatory effects through the newly identified AMPK-independent ceramidase activation pathway. Aberrant accumulation of ceramide, promotes a diverse array of activities related to metabolic disease, such as insulin resistance and fibrosis [91]. Ceramidase is a key enzyme converting ceramide to sphingosine-1-phosphate (S1P), an anti-inflammatory molecule. S1P has been implicated in a multitude of cellular responses such as cell proliferation and survival, migration and modulation of inflammatory reactions, which are critically involved in the mechanism underlying chronic inflammatory and fibrotic diseases [92]. Interestingly, APN potently stimulates a ceramidase activity to enhance ceramide catabolism and S1P formation by activating its cognate receptors AdipoR1 and AdipoR2. APN-regulated S1P can attenuate progression of fibrotic diseases through its anti-apoptotic and anti-inflammatory effects by inhibiting TNFα-induced inflammatory response, upregulating COX2 [93] and cross-activating the TGFβ/Smad signaling cascade via sphingosine kinase 1 (SphK1), which depletes TGFβ-induced CTGF expression [94] and positively regulates autophagy [95].
Transcriptional control and transcriptomic analysis of lipid metabolism in skin barrier formation and atopic dermatitis (AD)
Published in Expert Review of Proteomics, 2019
Nilika Bhattacharya, Gitali Ganguli-Indra, Arup K. Indra
The exogenous CER recycling route is involved in breaking down of the short-chain CER species, enabling its conversion to sphingosine. Particularly, the mRNA expression level of neutral ceramidase 2 (Asah2) and alkaline ceramidase 1 (Acer1) were found to be downregulated at all developmental stages in the mutant epidermis, being reduced by 0.7-fold and 0.4-fold, respectively, at E16.5, by 0.3-fold and 0.5-fold, respectively, at E17.5, and both by 0.5-fold at E 18.5. However, all other members of acid ceramidases (Asah1 and Asah3) and alkaline ceramidases (Acer2 and Acer3) showed unaltered expression in embryos across all stages of skin organogenesis [23].