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.