Epidermal Dysfunction Leads to an Age-Associated Increase in Levels of Serum Inflammatory Cytokines

Abstract

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, as well as 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 led 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 increased in otherwise normal, aged mice (>12 months). Third, expression of TNFα and amyloid A mRNA levels increased in the epidermis, but not in the liver, in parallel with significant elevations 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 the 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.

Topical applications of an emollient reduce circulating pro‐inflammatory cytokine levels in chronically aged humans: a pilot clinical study

“…However, whether ageing causes inflammation or vice versa is not clear. At least in the skin, we postulated that ageing compromises epidermal functions, leading to productions of pro‐inflammatory cytokines because a) aged skin displays multiple functional abnormalities, including compromised permeability barrier homeostasis, elevated SC pH and reductions in SC hydration, which all can increase pro‐inflammatory cytokine production, and b) improvements in epidermal function can lower levels of pro‐inflammatory cytokines in both the skin and circulation . Despite the evidence from this pilot study, this hypothesis remains to be validated in future studies.…”

“…Because these elevations in cytokine expression could eventually provoke systemic inflammation, improvements in epidermal function could in theory prevent and/or mitigate systemic inflammation. Chronologically aged mice, with no clinical evidence of inflammation, exhibit cutaneous functional abnormalities, which are accompanied by elevated levels of certain cytokines in the skin and circulation . Pertinently, disruption of epidermal permeability barrier function by repeated tape‐stripping, and following acute exposure to erythemogenic UV‐B provoke increases in the levels of cutaneous and circulating cytokines, including IL‐1β, IL‐6 and TNFα …”

“…Our recent studies showed that improving epidermal functions in chronologically aged mice skin normalizes not only cutaneous, but also serum levels of cytokines . In this pilot study, we show that topical applications of a physiologic lipid‐containing emollient, known to improve epidermal function in humans, normalized circulating levels of key pro‐inflammatory cytokines, closely associated with the development of chronic diseases in otherwise normal aged humans.…”

“…We showed further that disruption of the epidermal permeability barrier provokes (i) an increase in cutaneous cytokine production; and (ii) an increase in serum cytokine levels, independent of hepatic or T‐cell involvement . Moreover, chronologically aged mice display elevations in both cutaneous and circulating levels of cytokines; and directly pertinent to this study, improving epidermal function in aged mice reduced cutaneous, as well as circulating levels of three key, age‐associated cytokines . In this proof‐of‐concept preliminary pilot study, we assessed whether improving epidermal function with an emollient, containing a mixture of lipids that mimics the components of normal SC, lowers circulating levels of these same pro‐inflammatory cytokines in aged humans.…”

“…While the aetiology of this age‐associated, systemic inflammation remains uncertain, our recent studies have shown that both aged human and mouse skin display sustained abnormalities in epidermal permeability barrier homeostasis, stratum corneum (SC) hydration, and elevations in SC pH, each of which has been shown to independently provoke cutaneous inflammation. We showed further that disruption of the epidermal permeability barrier provokes (i) an increase in cutaneous cytokine production; and (ii) an increase in serum cytokine levels, independent of hepatic or T‐cell involvement . Moreover, chronologically aged mice display elevations in both cutaneous and circulating levels of cytokines; and directly pertinent to this study, improving epidermal function in aged mice reduced cutaneous, as well as circulating levels of three key, age‐associated cytokines .…”