Stress-induced modulation of skin immune function: two types of antigen-presenting cells in the epidermis are differentially regulated by chronic stress.

Abstract

Inflammatory skin diseases are exacerbated by psychiatric stress. Previous studies have shown that the activity of epidermal antigen-presenting cells (APCs), Langerhans cells (LCs) and keratinocytes (KCs), is affected by stress. Hapten application causes migration of LCs to draining lymph nodes (DLNs). Recently, we found that hapten application also activates epidermal cells (ECs) to mature potent APCs, and that the main APCs in these populations are KCs. Thus, DLN cells and ECs following hapten application are available for estimating the APC function of LCs and KCs in stress studies. To investigate the mechanism of exacerbation of skin inflammation by chronic stress by observing the effect of isolation stress transversally on the skin immune and neurohormonal systems. Contact sensitivity (CS) was elicited in BALB/c mice. The APC function of LCs and ECs following hapten application was assessed by the CS-inducing activity in the recipient mice. Levels of neurohormonal transmitters and proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. Cell surface molecules were detected using flow cytometry. Expression of mRNA for cytokines, neurohormonal receptors and a differentiation marker by ECs was determined by reverse transcription-polymerase chain reaction. Acute stress (2-day isolation) suppressed induction of CS, while chronic stress (30-day isolation) markedly enhanced induction of CS. DLN cells from chronically stressed mice contained increased numbers of LCs and exhibited enhanced APC function for inducing CS. In contrast, the APC function of KCs from these mice was markedly suppressed. Serum corticosterone levels were enhanced in acute stress, while substance P (SP) levels were enhanced in chronic stress. Corticotrophin-releasing hormone receptor-1 mRNA expression in ECs was enhanced in acute stress, while SP receptor (i.e. neurokinin-1 receptor) mRNA expression in ECs was enhanced in chronic stress. Production and mRNA expression of the proinflammatory cytokines interleukin-1 alpha and tumour necrosis factor-alpha by ECs following hapten application was markedly suppressed in chronic stress. Expression by ECs of E-cadherin, which adheres LCs and KCs homophilically, was suppressed in chronic stress. In addition, these cells exhibited impaired differentiation, i.e. suppressed spontaneous proliferation and enhanced mRNA expression for transglutaminase-3. Chronic isolation stress may enhance CS responses by upregulation of the APC activity of LCs and the SP system. However, dysregulation of KC function and differentiation by chronic stress suggests that KCs may not contribute to the enhancement of the CS response positively. These complex changes suggest that chronic isolation stress in mice may provide a possible model system for studying the mechanism of exacerbation of skin inflammation by stress.