Figure legendsFigure 1. IL-31 signaling via its cognate IL31RA/OSMRβ receptor heterodimer. Binding of IL-31 leads to receptor dimerization, cytosolic phosphorylation and subsequent activation of canonical kinase pathways including JAK/STAT, PI3K/AKT and MAPK cascades. Note that OSMRβ specific recruitment of the adapter proteins SHC and SHP-2 facilitates phosphorylation and activation of various MAPK cascade members. Dependent on cell type and cell environment, downstream transcription factor activation subsequently controls the expression of genes involved in inflammation, proliferation and cell survival.Figure 2. Illustration depicting the effects of IL-31 in atopic dermatitis skin. CLA+ TH2 cells are abundant allergen-reactive T cells in the circulation of AD patients and are recruited to the AD-affected skin through CCL17 and CCL22 signaling. In the skin, CLA+ TH2 cells secrete IL-31, which in turn can activate IL31RA/OSMRβ-expressing cutaneous sensory nerves, innate immune cells including DCs, monocytes and eosinophils (not shown) and keratinocytes of the epidermis. In human AD skin, keratinocytes show elevated levels of IL31RA/OSMRβ expression resulting in stronger receptiveness to IL-31. Cutaneous IL-31 signaling results in peripheral pruritus, (neuro)-inflammation and an impaired barrier function through IL-31-mediated suppression of terminally differentiated genes such as filaggrin and a reduced lipid envelope. Activated keratinocytes secrete various chemo-attractants that trigger an additional recruitment of IL-31-expressing CLA+TH2 cells to the site of inflammation, nurturing a feedback-in loop of skin inflammation and pruritus. Human and mouse sensory neurons express IL31RA/OSMRβ mostly in neurons that also co-express TRPV1. Sensory nerve endings demonstrate high IL31RA levels in AD skin and IL-31 stimulation leads to enhanced neuronal growth probably causing pruritic hypersensitivity and an elevation of peripheral pruritus. In the central nervous system, IL31RA/OSMRβ immunoreactivity has been shown in the dorsal horn of the spinal cord, indicating that IL-31 signaling is likely involved in central pruritus and sensitization of spinal cord neurons.Figure 3. IL-31 Function in Mucosal Sites.