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    • The multiple functions that are impacted by the

    2018-11-12

    The multiple functions that are impacted by the epidermal structural protein, filaggrin, serve as another illustrative example of the link between multiple defense functions. First, the full-length protein becomes a component of the CE, contributing to epidermal mechanical defense. We have shown that an intact CE is required for the supramolecular organization of secreted lipids into lamellar bilayers, as eloquently demonstrated in two disorders of cornification, transglutaminase 1-deficient lamellar ichthyosis and loricrin keratoderma. But it is the subsequent, humidity-dependent proteolysis of FLG above the mid-SC that impacts an even broader suite of functions (Figure 7). Following FLG hydrolysis, its constituent alk inhibitor are further deiminated, both enzymatically and nonenzymatically, into a suite of polycarboxylic acids (“natural moisturizing factor”) that not only account for much of SC hydration, but also contribute to defense against UV-B and to the acidification of the SC (Figure 7). The reduced pH of the SC, in turn, is critical for multiple functions, including not only antimicrobial defense, but also permeability barrier homeostasis, SC cohesion, and proinflammatory cytokine activation. We next highlight another example of linked functions that recently emerged from the laboratory of Sabine Werner (Institute of Cell Biology, Zurich, Switzerland), who showed that a key transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), regulates the expression of two CE precursors, small proline-rich proteins (Sprr2b and Sprr2h). This transcription factor also regulates expression of a potent antimicrobial protein, secretory leukocyte protease inhibitor (Slpi), which is also an inhibitor of serine proteases (kallikreins) that regulate SC cohesion (Figure 8). The cohesiveness of the SC, in turn, is critical for both permeability barrier function and antimicrobial defense. Together, these examples of functional links illuminate how discrete epidermal protective functions should instead be considered components of a broader, protective “superfunction” of the skin.
    Metabolic mechanisms that maintain epidermal homeostasis We view one of our standard laboratory models, i.e., sequential tape stripping, as a type of superficial wound. Tape stripping (no different than either detergent or solvent wipes) produces a defect in the permeability barrier, and all three of these unrelated, acute perturbations stimulate an identical series of metabolic responses in the underlying epidermis that rapidly re-establishes permeability barrier homeostasis in a predictable sequence, and with characteristic kinetics (Table 3). This approach (which we term the cutaneous stress test or “treadmill of the skin”) can be deployed to identify specific metabolic responses that bring about reestablishment of barrier homeostasis. The earliest response to acute barrier perturbations is the immediate secretion (within 15–20 minutes) of much of the preformed pool of LBs from cells of the outer SG. After exteriorizing their cargo of LB contents, these outermost SG cornify, i.e., they undergo physiologic apoptosis, followed immediately by the apical migration of subjacent SG cells (Table 3). Yet, barrier perturbations also stimulate injury responses that may be unrelated to the restoration of barrier function. To distinguish among these two events, one can artificially restore barrier function with a vapor-impermeable wrap, such as a Latex glove or a sheet of Saran wrap. By sending a “message” that the barrier function is now normal, these forms of occlusion shut down metabolic events that are solely directed at restoring barrier function, including virtually all of the changes shown in Figure 9 and Table 3. Yet, some responses, such as increased cytokine production (see below), are not blocked by occlusion. These could be dual-purpose, i.e., signals of both barrier homeostasis and an injury response. Finally, it should be noted that the same “stress test” approach has allowed us to identify abnormalities in barrier function in the following: (1) developmental (neonatal and aged skin) settings; (2) human populations, subjected to psychological stress, or endowed with different pigment types; and (3) disease settings. Finally, the stress test led to the development of new generations of “barrier repair” therapeutics as well as novel metabolically based, drug delivery technologies.