Alterations in cytokine regulation in aged epidermis: implications for permeability barrier homeostasis and inflammation

Abstract

Acute disruption of the cutaneous permeability barrier with either solvents or tape-stripping stimulates a homeostatic metabolic response in the subjacent nucleated layers of the epidermis that results in a rapid restoration of normal permeability barrier function. When the aged epidermal permeability barrier is stressed, it reveals a diminished capacity for recovery, in comparison to young epidermis, analogous to other organs in the aged when stressed. Although the signals that regulate this homeostatic response by the epidermis have not yet been resolved, acute permeability barrier disruption stimulates release of prestored IL-1alpha, and increased production of potentially regulatory cytokines, including IL-1alpha and TNFalpha in the epidermis. In these studies, we addressed the hypothesis that cytokine dysregulation explains the permeability barrier abnormality in aged epidermis, assessing the regulation of IL-1 and TNF signaling in aged vs young mice. To determine whether the IL-1 family of cytokines plays a key role in the permeability barrier abnormality of the aged, permeability barrier recovery rates were compared in transgenic mice lacking the functional IL-1 type 1 receptor vs wild-type mice at various ages. Knockout of the IL-1 type 1 receptor exacerbates the defect in permeability barrier homeostasis that is seen in age-matched, wild-type counterparts. Furthermore, the sluggish permeability barrier recovery in aged epidermis is associated with, and at least in part attributable to, altered expression of the IL-1 family of cytokines and receptors both under basal conditions and after acute barrier perturbations. Whereas modulations in cytokine expression with epidermal permeability barrier perturbation are qualitatively similar in aged epidermis, they greatly differ quantitatively. In contrast, examination of TNFalpha mRNA and protein basally, and following barrier perturbation revealed no alterations in aged epidermis. Together, these results show that selective alterations in the IL-1 family of cytokines occur with aging and that defects in IL-1 signaling may contribute to the epidermal permeability barrier abnormality of aged skin.

Impact of Age and Body Site on Adult Female Skin Surface pH

“…Interestingly, the omega-3 polyunsaturated fatty acid 11,14,17-eicosatrienoic acid was found to be increased in photoaged human epidermis and also after UV irradiation, whereas a decrease was found in intrinsically aged human epidermis [33]. A deficiency of IL-1 signaling in murine aged epidermis, which may contribute to epidermal barrier abnormality, has been reported by Ye et al [23]. An improvement in barrier recovery has been achieved with the administration of imiquimod to aged murine skin, as imiquimod induces an alteration in multiple cytokine pathways, including an increase in IL-1α levels, and this seems to improve barrier recovery in aged epidermis [23,34].…”

“…Choi et al showed that the increased vulnerability of aged skin is due to abnormal SC acidity, resulting in defective lipid processing and loss of SC integrity [16]. Table 1 summarizes known changes in epidermal barrier function during aging [9,16,17,18,19,20,21,22,23,24], which may affect pH SC and pH SS .…”

Skin and brain age together: The role of hormones in the ageing process

“…The number or function of T cells and B cells deteriorate (Effros, 2001;Gardner and Murasko, 2002;Grubeck-Loebenstein and Wick, 2002) while the effects of age on innate immune cells, such as macrophages have been widely investigated (Plackett et al, 2004). In human skin, cytokine dysregulation, particularly of the interleukin (IL)-1 family has been described to contribute to ageing (Ye et al, 2002) and disturbed skin barrier function. The microinflammatory model of skin ageing postulates that every stimulus able to induce the synthesis of intercellular adhesion molecule-1 (ICAM-1) in the endothelium is a factor of skin ageing.…”

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

“…Although cholesterol synthesis rates are high under basal conditions, following permeability barrier disruption, epidermal cholesterol synthesis increases ( 3 ), as do the levels of receptors such as the LDL receptor and scavenger receptor class B, member 1 that enhance the uptake of cholesterol into keratinocytes ( 4, 5 ). Inhibition of cholesterol synthesis perturbs permeability barrier function ( 6 ), and a selective deficiency in cholesterologenesis largely accounts for the barrier abnormality in chronologically aged epidermis ( 7,8 ). Cholesterol is also the precursor of an important bioregulatory molecule in keratinocytes, cholesterol sulfate (CS), which regulates epidermal keratinocyte differentiation ( 9-11 ) and corneocyte desquamation by diverse mechanisms ( 12, 13 ).…”