Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, β-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression.

Acute psychological stress (PS) mobilizes metabolic responses that are of immediate benefit to the host, but the current medical paradigm holds that PS exacerbates systemic and cutaneous inflammatory disorders. Although the adverse consequences of PS are usually attributed to neuroimmune mechanisms, PS also stimulates an increase in endogenous glucocorticoids (GCs) that compromises permeability barrier homeostasis, stratum corneum cohesion, wound healing, and epidermal innate immunity in normal skin. Yet, if such PS-induced increases in GC were uniformly harmful, natural selection should have eliminated this component of the stress response. Hence, we hypothesized here instead that stress-induced elevations in endogenous GC could benefit, rather than aggravate, cutaneous function and reduce inflammation in three immunologically diverse mouse models of inflammatory diseases. Indeed, superimposed exogenous (motion-restricted) stress reduced, rather than aggravated inflammation and improved epidermal function in all three models, even normalizing serum IgE levels in the atopic dermatitis model. Elevations in endogenous GC accounted for these apparent benefits, because coadministration of mifepristone prevented stress-induced disease amelioration. Thus, exogenous stress can benefit rather than aggravate cutaneous inflammatory dermatoses through the anti-inflammatory activity of increased endogenous GC.

Multilayered human keratinocyte cultures increasingly are used to model human epidermis. Until now, studies utilizing human epidermal equivalents (HEEs) have been limited because previous preparations do not establish a normal epidermal permeability barrier. In this report, we show that reducing environmental humidity to 50% relative humidity yields HEEs that closely match human postnatal epidermis and have enhanced repair of the permeability barrier. These cultures display low transepidermal water loss and possess a calcium and pH gradient that resembles those seen in human epidermis. These cultures upregulate glucosylceramide synthase and make normal-appearing lipid lamellar bilayers. The epidermal permeability barrier of these cultures can be perturbed, using the identical tools previously described for human skin, and recover in the same time course seen during in vivo barrier recovery. These cultures will be useful for basic and applied studies on epidermal barrier function.

The cutaneous permeability barrier is essential for life and perturbations in this barrier are repaired rapidly. After minimal injury to the stratum corneum alterations in the calcium concentration in the outer epidermis are the primary signal inducing this repair response. In this issue, studies demonstrate that Toll-like receptor 3 has an important role in signaling permeability barrier repair following injury induced by UVB irradiation.

BACKGROUND

High-density lipoprotein (HDL) particles have properties beyond reverse cholesterol transport. We hypothesized that their protection extends to inflammation-related disease. The predictive value of HDL particle subclasses and inflammatory markers was studied for noncardiovascular, noncancer chronic inflammation-related death and hospitalization, and for incident cardiovascular disease (CVD).

METHODS AND RESULTS

A multiethnic, multicenter, prospective observational study was conducted in 6475 men and women (aged 45 to 84 years) free of known CVD at baseline with median follow-up of 10.1 years. Fasting venous samples were analyzed for baseline lipid profile and lipoprotein particles. We focused on the HDL family of variables (small-, medium-, and large-diameter HDL particles and HDL cholesterol). Analyses identified the sum of small- plus medium-diameter HDL particles as important. Small- plus medium-diameter HDL particles were inversely associated with diagnostic code-based noncardiovascular, noncancer chronic inflammation-related death and hospitalization (n=1054) independent of covariates: relative risk per SD 0.85 (95% CI: 0.79 to 0.91, P<0.0001). Small- plus medium-diameter HDL particles were also associated with adjudicated fatal and nonfatal coronary heart disease events (n=423): relative risk per SD 0.88 (95% CI 0.77 to 0.98, P=0.02).

CONCLUSIONS

Small- plus medium-diameter HDL particles are an independent predictor for noncardiovascular, noncancer chronic inflammation-related death and hospitalization and for coronary heart disease events in subjects initially free of overt CVD. These findings support the hypothesis that smaller HDL particles of diameter <9.4 nm have anti-inflammatory properties in the general population.

Even though elderly populations lack visible or other clinical signs of inflammation, their serum cytokine and C-reactive protein levels typically are elevated. However, the origin of age-associated systemic inflammation is unknown. Our previous studies showed that abnormalities in epidermal function provoke cutaneous inflammation, and because intrinsically aged skin displays compromised permeability barrier homeostasis and reduced stratum corneum hydration, we hypothesized here that epidermal dysfunction could contribute to the elevations in serum cytokines in the elderly. Our results show first that acute disruption of the epidermal permeability barrier in young mice leads not only to a rapid increase in cutaneous cytokine mRNA expression but also an increase in serum cytokine levels. Second, cytokine levels in both the skin and serum increase in otherwise normal, aged mice (>12 months). Third, expression of tumor necrosis factor-α and amyloid A mRNA levels increased in the epidermis, but not in the liver, in parallel with a significant elevation in serum levels of cytokines. Fourth, disruption of the permeability barrier induced similar elevations in epidermal and serum cytokine levels in normal and athymic mice, suggesting that T cells play a negligible role in the elevations in cutaneous and serum inflammatory cytokines induced by epidermal dysfunction. Fifth, correction of epidermal function significantly reduced cytokine levels not only in the skin but also in the serum of aged mice. Together, these results indicate that the sustained abnormalities in epidermal function in chronologically aged skin contribute to the elevated serum levels of inflammatory cytokines, potentially predisposing the elderly to the subsequent development or exacerbation of chronic inflammatory disorders.