The IL-31 axis in the skin
The role of the IL-31/IL31RA axis in pruritus and pruritic disorders such as AD is firmly accepted, although precise aspects about the pathophysiological role of IL-31 signaling remain to be elucidated. In humans, IL-31 acts as a pruritogen but evokes a rather late itch response when applied intradermally.50 In AD patients, serum IL-31 and IL-33 levels are found to be increased when compared to healthy volunteers, nurturing the hypothesis that IL-33 might stimulate the secretion of IL-31 from TH2 cells or epithelial cells in vivo.51 In the skin, IL-31 enforces tissue alterations that are typically seen in AD patients (Figure 2). A recent study associated IL-31 with epidermal thickening as well as impaired skin barrier function and impaired mechanical integrity due to reduced junction plakoglobin (Jup ) gene expression.52 In organotypic skin models, IL-31 signaling induced differentiation defects depicted by the deficit in filaggrin expression and a reduction of the lipid envelope.53 Gene expression analysis confirmed a direct IL-31 dependent regulation of genes involved in skin barrier and identified the IL-1 cytokine network as a downstream effector of IL-31 signaling.54 Accordingly, anakinra-mediated IL1R blockage was effective to abrogate IL-31-mediated loss of skin differentiation. However, complete inhibition of IL-31 signaling might not be a desirable therapeutic outcome, since low doses of IL-31 are needed for the release of antibacterial peptides from keratinocytes.54
In vitro data from mouse keratinocytes suggest involvement of IL-31 in immune-cell recruitment, an important process during AD development. IL-31 initiates the release of various immune cell-attracting chemokines such as CCL4, CCL17, CCL22 and CCL25.1 CCL17 and CCL22, for instance, recruit cutaneous lymphocyte antigen (CLA+)-expressing T cells to the epidermis. This immune cell subset is of major interest in AD since CLA+ T cells are abundant allergen-reactive T cells in the circulation and lesional skin of AD-affected patients.55 Whether IL-4- and IL-13-producing CLA+ CD3+ T cells or specific subtypes express IL-31 is not known but anticipated. However, the epidermis of AD-derived skin expresses elevated levels of IL31RA and forms a ‘sensitized’ target for IL-31.10‘AD-conditioned’ keratinocytes could perpetuate the recruitment of CLA+, probably IL-31+-TH2 cells to the skin via release of chemokines, which in turn further activate keratinocytes via IL-31, thereby completing a positive feedback loop between the skin and immune system communication (Figure 1). That circuit would result in the progression of inflammation, pruritus and impaired skin barrier, thus progression of AD. The critical factor(s) that modulate(s) epidermal IL31RA expression levels in AD in vivo is not known yet. However, pro-inflammatory signals such as IFNγ or neuropeptides like BNP are candidates, highlighting the importance of functional IL-31 in pro-inflammatory environments.23,24,56
Recent observations emphasize the importance of skin-resident memory T cells (CD3+ CD45RO+CLA+) for AD onset.10,57–59 Most of the skin-resident memory T cells are antigen-experienced and expresses the surface histocompatibility antigen-DR (HLA-DR). Challenge of this T cell subset with AD-associated bacterial superantigens such as staphylococcal enterotoxins B (SEB) or house dust mites (HDM)-derived antigens enhances the effector phenotype of the cutaneous TH2 pool.60,61 Such priming and expansion of skin-resident memory T cells by antigens originating from skin-colonizing Staphylococcal aureus (SA) and HDM is a common observation in AD patients. Recently, elevated frequencies of HDM-reactive IL-31+ T cells were observed in the periphery of chronic AD patients associated with decreased TH1/TH2 and Tc1/Tc2 ratios.62 This finding indicates that allergen-specific T cells are subject to pre-existing TH2-Tc2 and that IL-31 may be involved in TH31-Tc31 programming.62 The capacity of SA-specific T cells to produce and secrete IL-31 has not been tested yet. However, SEB is known to activate multiple T cell subsets, to act nonspecifically, and thereby might be ineffective to expand an IL-31+ T cell subset.56,60 A more general stimulation of toll-like receptor (TLR)-2 by bacterial cell wall components or ‘atopic’ cytokines increased IL31RA- and OSM-expression levels as well as CCL2 release in human keratinocytes, linking IL-31 to skin colonization and innate immunity.56 Priming of T cells, however, is a complex process, which relies on an intricate interplay between the innate and adaptive immune system. Patrolling phagocytes of the adaptive immune system recognize via TLRs or pattern-recognition receptors (PRRs) invading pathogens or allergens and present them to cells of the adaptive immune system, such as CD4+ T helper cells. The most effective antigen-presenting cells (APCs) are tissue resident dendritic cells (DCs), which capture the antigen and - depending on the subsequent activation of the respective TLR - activate either effector or regulatory T cells. Like keratinocytes, exposure of primary human CD1c+ and monocyte-derived dendritic cells to IL-31 results in STAT-1 activation and subsequent IL31RA increase.63 IL-31-stimulated dendritic cells secrete an extensive number of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα), IL-6, IL-8 and chemokines such as CCL2, CCL5 and CCL22, leading to amplified tissue inflammation.63DC-derived cytokines induce a massive influx of immune cells including TH2 cells and eosinophils. A recent study reports that eosinophils express IL31RA,64 and that IL-31 functions as a survival signal lowering the rate of apoptosis in these cells.65 Thus, IL-31 signaling may offer a survival advantage to AD-associated eosinophils reinforcing the inflammatory cascade. Uncontrolled clonal expansion of effector T cells leads to the recruitment of additional eosinophils and CD68+macrophages.10 Finally, activated DCs participate in the activation of CD4+ T cells, including TH2 cells, by presenting SEB- or HDM-antigen to tissue-resident or infiltrated naïve T-cells.