Acute Modulations in Permeability Barrier Function Regulate Epidermal Cornification

Abstract

Stratum corneum comprises corneocytes, derived from outer stratum granulosum during terminal differentiation, embedded in a lipid-enriched extracellular matrix, secreted from epidermal lamellar bodies. Permeability barrier insults stimulate rapid secretion of preformed lamellar bodies from the outer stratum granulosum, regulated through modulations in ionic gradients and serine protease (SP)/protease-activated receptor type 2 (PAR2) signaling. Because corneocytes are also required for barrier function, we hypothesized that corneocyte formation could also be regulated by barrier function. Barrier abrogation by two unrelated methods initiated a wave of cornification, assessed as TdT-mediated dUTP nick end-labeling-positive cells in stratum granulosum and newly cornified cells by electron microscopy. Because cornification was blocked by occlusion, corneocytes formed specifically in response to barrier, rather than injury or cell replacement, requirements. SP inhibitors and hyperacidification (which decreases SP activity) blocked cornification after barrier disruption. Similarly, cornification was delayed in PAR2

Moisturizers versus Current and Next-Generation Barrier Repair Therapy for the Management of Atopic Dermatitis

“…It would be logical to deploy KLK inhibitors, many of which are naturally-occurring, such as α1-anti-trypsin inhibitor or soybean trypsin inhibitor. KLKs not only are directly destructive, but they also bind to and activate plasminogen activator type 2 receptor (PAR 2 ), which in turn blocks lamellar body secretion [43] and provokes pruritus [44]. Hence, small peptide inhibitors of PAR2 could yet enter the therapeutic armamentarium for AD.…”

Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

“…Moreover, as in AD, the pH of SC is elevated in IV 19,20 , and the increase in pH, in turn, could activate serine proteases (kallikreins), with a host of negative downstream consequences, including: a) plasminogen activator type 2 receptor (PAR2)-mediated blockade of LB secretion 21,22 ; b) possible downstream alterations in keratin filament organization that could impede LB secretion (see below); and c) both Th1-and KLK5-activated Th2 inflammation 23 (Figs. 2, 3).…”

Asian dust storm particles induce a broad toxicological transcriptional program in human epidermal keratinocytes

“…Caspase-14 (CASP14) is expressed in terminally differentiating keratinocytes and can regulate filaggrin metabolism in the epidermis. Therefore, CASP14 in HEK is important in regulating skin hydration and cornification of the stratum corneum (Demerjian et al, 2008;Denecker et al, 2008). ADSPs significantly increased CASP14 mRNA expression while other apoptosis-related cysteine proteases like caspase-3, -8, and -9 were unaffected (Table 1).…”