Severe dermatitis with loss of epidermal Langerhans cells in human and mouse zinc deficiency

Abstract

Zinc deficiency can be an inherited disorder, in which case it is known as acrodermatitis enteropathica (AE), or an acquired disorder caused by low dietary intake of zinc. Even though zinc deficiency diminishes cellular and humoral immunity, patients develop immunostimulating skin inflammation. Here, we have demonstrated that despite diminished allergic contact dermatitis in mice fed a zinc-deficient (ZD) diet, irritant contact dermatitis (ICD) in these mice was more severe and prolonged than that in controls. Further, histological examination of ICD lesions in ZD mice revealed subcorneal vacuolization and epidermal pallor, histological features of AE. Consistent with the fact that ATP release from chemically injured keratinocytes serves as a causative mediator of ICD, we found that the severe ICD response in ZD mice was attenuated by local injection of soluble nucleoside triphosphate diphosphohydrolase. In addition, skin tissue from ZD mice with ICD showed increased levels of ATP, as did cultured wild-type keratinocytes treated with chemical irritants and the zinc-chelating reagent TPEN. Interestingly, numbers of epidermal Langerhans cells (LCs), which play a protective role against ATP-mediated inflammatory signals, were decreased in ZD mice as well as samples from ZD patients. These findings suggest that upon exposure to irritants, aberrant ATP release from keratinocytes and impaired LC-dependent hydrolysis of nucleotides may be important in the pathogenesis of AE.

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…The molecular basis underlying the severe dermatitis in AE patients was recently shown (204). In this study, irritant contact dermatitis through loss of Langerhans cells is revealed to cause dysregulation of ATP- mediated inflammatory signals (204). Zinc-deficient phenotypes in AE patients can be ameliorated with a simple, daily oral zinc supplementation (1-3 mg·kg Ϫ1 ·day Ϫ1 ) (362).…”

P2X7 receptor in skin biology and diseases

“…Notably, CD39 on LCs has been implicated in facilitating a protective or tolerogenic role for these cells in dermatitis [33,36] . Collectively, variations in CD39 activity may play important roles in the regulation of P2X7 activation on LCs, and in determining the relative contribution of these cells in immunity or peripheral tolerance.…”

“…Croton oil also decreases ATPDase activity in mice [20] indicating that chemical irritants may further potentiate P2X7-mediated responses by causing a sustained increase in ATP concentrations during chemical irritant exposure. Of note, zinc deficiency, which is often associated with increased cutaneous inflammation, enhances ICD in mice and augments chemical irritant-induced ATP release from murine keratinocytes and in murine skin [36] . Further, zinc deficiency in murine ICD is associated with loss of LCs [36] , which play a protective role in ICD through CD39 expression [33] .…”

“…Of note, zinc deficiency, which is often associated with increased cutaneous inflammation, enhances ICD in mice and augments chemical irritant-induced ATP release from murine keratinocytes and in murine skin [36] . Further, zinc deficiency in murine ICD is associated with loss of LCs [36] , which play a protective role in ICD through CD39 expression [33] . This suggests that both increased ATP release from keratinocytes and impaired hydrolysis of ATP by LCs may contribute to the pathogenesis of ICD.…”

Overview of Inherited Zinc Deficiency in Infants and Children

“…Pathogenic mutations in AE have been shown to result in defects in zinc responsive trafficking to the plasma membrane, reduced zinc uptake activity (16), or defects in processing, in which the extracellular aminoterminal domain of ZIP4 undergoes proteolytic cleavage during extended periods of zinc deficiency (17). The molecular mechanism causing severe dermatitis, which is one of the primary features in AE patients and severe zinc deficiency, has been shown not to be attributable to allergic contact dermatitis, but irritant contact dermatitis, which is caused by loss of Langerhans cells with a protective role against ATP-mediated inflammatory signals (18). However, those causing alopecia and diarrhea in AE patients remain unknown.…”