Impaired Sphingomyelinase Activity and Epidermal Differentiation in Atopic Dermatitis

Abstract

A defective permeability barrier leads to the penetration of environmental allergens into the skin and initiates immunological reactions and inflammation crucially involved in the pathogenesis of atopic dermatitis (AD). Decreased stratum corneum ceramide content may cause the defect in permeability barrier function consistently found in AD. Acid and neutral sphingomyelinase (A- and N-SMase) generate ceramides with structural and signal transduction functions in epidermal proliferation and differentiation. We determined epidermal SMase activities, DNA synthesis, involucrin, loricrin, filaggrin, and keratin expression in lesional and non-lesional skin of AD patients. We found decreased epidermal A-SMase activity in lesional and non-lesional skin, correlating with reduced stratum corneum ceramide content and disturbed barrier function. N-SMase activity was reduced in non-lesional skin and more significantly reduced in lesional skin, correlating with impaired expression of cornified envelope proteins and keratins, important for skin barrier function. Changes in involucrin, loricrin, filaggrin, keratin K 5 (basal) and K 16 (proliferation associated) were noticed in non-lesional and lesional skin, whereas changes in K 10 (suprabasal), K 6 (proliferation associated), and K 17 (inflammation associated) were found only in lesional skin. In summary, reduction in SMase-generating ceramides and impaired differentiation are involved in the defective barrier function found in AD.

Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

“…This is contradictory to previous studies by Sugiara et al [28] and Jensen et al [29]. Using gene microarrays, Sugiara et al [28] observed increased IVL and decreased LOR gene expression in lesional AD skin.…”

“…This factor is not clearly defined in either of the previous studies [28,29]. AD lesions are bi-phasic with acute lesions having more of a Th2 cytokine milieu and chronic lesions having more of a Th1 cytokine milieu [19].…”

“…Using gene microarrays, Sugiara et al [28] observed increased IVL and decreased LOR gene expression in lesional AD skin. Jensen et al [29] observed increased LOR and decreased IVL expression using immunohistochemistry and western blotting. Important differences in experimental design may explain the discrepancies between our observations and those previously published: 1) while gene microarrays provide a significant amount of information, they are known to have limitations and can be falsely positive or negative [30,31].…”

Clinical correlations of recent developments in the pathogenesis of atopic dermatitis

“…LTA activated IDECs migrate to draining lymph nodes of skin to promote Th1 responses permeability barrier may be a result of an altered lipid composition, such as decreased ceramide, in the stratum corneum (SC). 26 Ceramides are major water retaining molecules present in the extracellular space of the cornified envelope. During the process of cornification, the ceramide containing bilayer is covalently attached to various proteins on the extracellular surface of the cornified envelope.…”

“…28 The mechanisms by which the ceramide content is altered include the decreased activity of epidermal acid sphingomyelinase (A-SMase) in lesional and non lesional skin which correlates with reduced SC ceramide content and defects in permeability barrier. 26 Recent studies have demonstrated that stress, which is a known exacerbator for AD, can have direct effects on skin barrier properties. Reports have demonstrated that insomniac psychologic stress affects epidermal cell proliferation, impairs epidermal differentiation and reduces the formation of lamellar bodies (LB) ultimately resulting in reduced synthesis of epidermal lipids such as cholesterol, fatty acid and ceramides.…”