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  • diacylglycerol kinase Introduction Too long viewed as a mere

    2018-11-15

    Introduction Too long viewed as a mere battleground for the immune system, the diacylglycerol kinase is asserting its rightful place at the center of cutaneous biology and pathophysiology. Although immunologists seek ever-finer distinctions between T cell subsets in inflammatory lesions, it is now increasingly clear that the protective requirements of the skin dictate virtually every metabolic process (including adaptive immune responses) in its underlying layers. True, there are “outside-to-inside-back-to-outside” vicious cycles, whereby immune responses further compromise epidermal function, and there are also examples of primary immune disorders, such as autoimmune and bullous diseases, human immunodeficiency virus (HIV) infections, and superantigen-initiated flares of erythrodermic psoriasis, where a primary inflammatory infiltrate can produce downstream abnormalities in epidermal function (e.g., for HIV, see Gunathilake et al). But, as the example of filaggrin-deficient atopic dermatitis (AD) eloquently demonstrates, most cutaneous immune phenomena occur downstream of primary epidermal insults, whether inherited or acquired, and these responses are recruited only when epidermal homeostatic responses fail to promptly reestablish normal cutaneous function. In this review, we consider: (1) a new “holistic” view of epidermal defense; (2) a concise review of the structural basis for the barrier with an update on tight junctions (TJs) and the corneocyte lipid envelope; (3) intraepidermal metabolic processes that are regulated by barrier requirements; (4) the role of homeostatic signaling mechanisms in regulating these responses; and (5) interrelated processes that impact disease pathogenesis.
    Brief review of barrier structure and function
    Interdependence of, and interrelationships between, epidermal defensive functions Although it is common practice to list the various defensive functions of the skin as discrete processes (Table 1), in most cases, these functions are interrelated, coregulated, and interdependent. As is evident from Figure 1, more and more connections are emerging between these defensive functions, of which we will highlight only a few for consideration here. Best appreciated are the connections between the permeability barrier and antimicrobial defense. Shared structural and biochemical, as well as common metabolic processes, unite these two functions (Table 2). Moreover, epidermal LBs provide a common delivery mechanism for components with overlapping functions, such as FFAs and antimicrobial peptides (Table 2), of which at least one, the cathelicidin carboxyterminal peptide, LL-37, is required not only to restrict pathogen invasion, but also as an apparent structural component of lamellar bilayers. In multiple clinical situations, in experimental perturbations, and after applications of therapeutic ingredients that either compromise or improve permeability barrier homeostasis, corresponding alterations occur in LL-37, and to a lesser extent, human beta-defensin 2 (hBD2) expression (Figure 3). LBs also deliver proteases and antiproteases that initially regulate SC cohesion, and then orchestrate the digestion of corneodesmosomes (Figures 4 and 5). However, corneodesmosome degradation is only the first in a series of subsequent cellular events that leads to the eventual shedding of corneocytes from the skin surface (Figure 5). Finally, as noted above, LBs also secrete at least two antimicrobial peptides, hBD2 and LL-37, into the SC extracellular domains. Because they appear to be so intertwined, it becomes a matter of semantics as to whether not only these two, but also whether several other functions, should be considered discrete or interrelated processes (Figure 1). There are pathogenic implications of LBs as an integrated delivery system. Not only permeability barrier function, but also antimicrobial defense and SC cohesion, are compromised in AD, and as shown in Figure 6 their altered gene products all converge on the LB secretory system.