Fluhr JW, Elias PM, Man M-Q et al.Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? J Invest Dermatol 130:2141-4

[1] Dermatology Service, Veterans Affairs Medical Center, San Francisco, California, USA [2] Bioskin, Berlin, Germany [3] Department of Dermatology, Charité University Clinic, Berlin, Germany.
Journal of Investigative Dermatology (Impact Factor: 7.22). 04/2010; 130(8):2141-4. DOI: 10.1038/jid.2010.74
Source: PubMed
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    • "The ‘acid mantle’ of the stratum corneum has a well-known antimicrobial effect and there is evidence that filaggrin breakdown products at physiological concentrations demonstrate an inhibitory effect on the growth of Staphyloccus aureus (Miajlovic et al., 2010). An acidic pH within the stratum corneum is also important for the functional activity of enzymes involved in ceramide metabolism (Fluhr et al., 2010). The acidic pH also modulates the activity of the serine protease cascade (Ovaere et al., 2009) required for co-ordinated epidermal differentiation and cornified cell envelope formation. "
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    ABSTRACT: The discovery, in 2006, that loss-of-function mutations in the filaggrin (FLG) gene are the cause of ichthyosis vulgaris-the most common disorder of keratinization-and also a strong genetic risk factor for atopic eczema, marked a significant breakthrough in the understanding of eczema pathogenesis. Subsequent investigations of the role of FLG-null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis, and peanut allergy. However, many questions remain to be answered in relation to the precise mechanisms by which deficiency of an intracellular protein expressed primarily in the differentiating epidermis may contribute to the development of cutaneous and systemic pathology. This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical, and therapeutic implications, and to consider possible future directions for ongoing investigation.
    Journal of Investigative Dermatology 12/2011; 132(3 Pt 2):751-62. DOI:10.1038/jid.2011.393 · 7.22 Impact Factor
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    • "However, the sPLA2-IB inhibitor used in that study, p-bromophenacyl bromide, also alkylates the active site histidine that is conserved in all sPLA2s and most likely inhibits multiple sPLA2s.53 A more recent study has shown that in filaggrin-deficient ft/ft mice, sPLA2-IIA is upregulated along with NHE1 expression, while sPLA2 forms -IIF and -X do not,1 contrasting with a previous study that demonstrated that sPLA2-IIA does not contribute to acidification and barrier function and sPLA2s-X is the main isoform to be secreted from keratinocytes.54 To assign more definitive roles to these isoforms, more enzyme-specific sPLA2s antibodies and inhibitors are needed, which in part will enable the identification of specific sPLA2s present within LB. "
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    ABSTRACT: The function of the epidermis is to form an effective barrier between the dry, external environment and the interior of the body. The barrier specifically resides in the extracellular lipid membranes of the stratum corneum (SC) and an acidic pH is necessary to maintain its competency against various insults. The purpose of this review is to explore the mechanisms which are postulated to contribute to the acidification of the stratum corneum, including both exogenous and endogenous sources. However, recent research as pointed to several endogenous mechanisms as the major source of acidification, including a sodium/proton pump (NHE1) and free fatty acid conversion from phospholipids by secretory phospholipase A(2) (sPLA(2)). sPLA(2) has been shown to play a central role in the formation of the SC "acid mantle" in the early maturation of the epidermis postnatally. Many aspects of this enzyme family are complex and still being elucidated in research and the most recent findings on the localization and functions of sPL A(2)-IB, -IIA, -IIC, -IID, -IIE, -IIF, -III, -V, -X and -XII in the epidermis are presented here. Given their role in inflammatory dermatoses, such as psoriasis and atopic dermatitis, understanding this complex enzyme family can lead to novel, life-changing therapies.
    Dermato-Endocrinology 04/2011; 3(2):84-90. DOI:10.4161/derm.3.2.15140
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    • "Filaggrin itself contributes to the epidermal barrier integrity by cross-linking the keratin filaments and the being degraded into a combined pool of highly hygroscopic amino acids, called the NMF, thereby contributing to the SC hydration. It is also postulated that filaggrin contributes to the formation of acid mantle within SC through the generation of urocanic acid via filaggrin-histidine-urocanic acid cascade.97 Therefore, filaggrin deficiency in AD lesion leads to defects in the formation of cornified envelope and a decreased ability of maintaining SC hydration and a concomitant elevation of pH. "
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    ABSTRACT: Proteases in the skin are essential to epidermal permeability barrier homeostasis. In addition to their direct proteolytic effects, certain proteases signal to cells by activating protease-activated receptors (PARs), the G-protein-coupled receptors. The expression of functional PAR-2 on human skin and its role in inflammation, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation, which is sustained by gene-environmental interactions. Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients. The imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/ PAR-2 signaling in AD. The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier. Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration. In addition, PAR-2 is an important sensor for exogenous danger molecules, such as exogenous proteases from various allergens, and plays an important role in AD pathogenesis. Together, these findings suggest that protease activity or PAR-2 may be a future target for therapeutic intervention for the treatment of AD.
    Yonsei medical journal 11/2010; 51(6):808-22. DOI:10.3349/ymj.2010.51.6.808 · 1.29 Impact Factor
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