IL-31 in neuro-immune communication
Multiple mediators including cytokines can induce pruritus (itch) which can develop into being intractable by nature, as seen in skin diseases or systemic disorders such as allergies, metabolic diseases or cancer.15–17 Peripheral nerve endings in the epidermis and dermis become activated by various endogenous or exogenous trigger factors during inflammation, allergies or systemic diseases.18,19 After activation of cytokine receptors on sensory nerve endings, like IL31RA, the nerves transmit the itch or pain signal to the central nervous system via the spinal cord and contralateral tractus spinothalamicus.20,21 Through an axon-reflex mechanism,22 neighbouring nerve branches become activated and release neuropeptides into the skin thereby inducing neurogenic inflammation, which can be also induced by IL-31.23,24 For example, IL-31 induced b-type natriuretic peptide (BNP) release from murine DRG neurons and skin cells mediated neuroinflammation by stimulating cytokine, chemokine and endothelin-1 (ET-1) release from keratinocytes.23,24Multiple pruritogens, their cognate receptors, channels and interaction networks have been identified.15,25–27 The capsaicin receptor TRP vanilloid receptor 1 (TRPV1) and mustard oil activated TRP ankyrin receptor 1 (TRPA1) are expressed on DRG neurons and are essential for the correct pruritic signal transmission of diverse pruritogens including IL-31.6,28–31 Together, these studies point at an essential role of IL-31 for the neuroimmune communication between TH2 cells, sensory nerves and keratinocytes, thereby initiating inflammation, epithelial dysregulation and pruritus, all characteristics of atopic dermatitis pathophysiology.
Cytokines have been found to act as pruritic sensitizers or activators, respectively, dependent on the concentration.32,33 In genetically modified mice, overexpression of only a single cytokine (demonstrated for IL-4, IL-13, IL-18, IL-31 or TSLP) is sufficient to cause pruritic AD-like skin lesions.25 In humans, our current knowledge points at IL-4 and IL-13 being the major molecular ‘drivers’ of AD.32,34 However, a transgenic mouse model demonstrated that overexpression of IL-31 is enough to initiate a severe AD-like phenotype with eczema and itch.1 In addition, implantation of GABAergic interneurons into the spinal cord of IL-31-overexpressing mice induced healing of skin lesions and alleviated pruritus.35 In AD patients, elevated expression levels of IL-31 and IL31RA were found in a significant amount of patients, but not all. While some patients showed high levels for IL-31 mRNA and IL31RA mRNA, others showed low levels for both, some low levels for either IL-31 or IL31RA.6 This result supports the hypothesis about AD being a clinically and molecular heterogenic disease in which patients differ with respect to their expression levels for IL-4, -13 and -31. This, of course, needs to be verified/falsified in the future.
Furthermore, IL31RA expression can be found in human dorsal root ganglia (sensory nerves), skin-infiltrating mononuclear cells and CD11b+ cells, establishing an important role of IL-31 in human AD as well. Considering that TH2 cells represent the main source of IL-31, the IL-31 axis could serve as a strong neuro-immune link between IL-31-expressing T cells and IL31RA-expressing sensory neurons.5,36 The receptor is predominantly expressed by small-to-medium size human DRG neurons (< 30 µm) co-expressing TRPV1 while large-diameter DRG neurons (< 50 µm) are mainly IL31RA-negative.36 In mice, both TRPV1 and TRPA1 ion channels are functionally linked to IL31RA since genetically (TRPV1, TRPA1 KO mice) or chemical blocking of TRPV1 can abrogate IL-31-mediated itch.6
A study conducting transcriptomics-based analysis in IL-31-activated DRG neurons revealed that IL-31 is further involved in neuronal proliferation, survival and metabolism.37Pump-equipped mice receiving a continuous IL-31 stimulus over weeks develop a denser cutaneous neural network than vehicle-treated control mice. The IL-31-mediated increase in cutaneous nerve fibre density is achieved by a STAT3-dependent increase in branching, extension and quantity of small-diameter sensory neurons along with the induction of neuronal survival via PI3K/AKT pathway activation.37These findings may partly explain the increased epidermal sensory nerve fibre density in AD patients.38–42 which probably accounts for the higher ‘skin sensitivity’ in AD patients to minimal stimuli. This is in line with the assumption that neural changes occur in direct response to on-going inflammatory signals in AD. However, a recent study conducted in a mouse model of AD utilizing continuousin vivo imaging of peripheral sensory nerves and blood vessels implicates that neural changes might preceed immune cell infiltration, vascularization and vascular permeability.40 The author suggests that ‘allergic stimulation in a chronic eczema model requires neural recruitment and activation early in the process for the initiation and maintenance of the inflammatory cascade’.40 With early neuronal imprinting established, subsequent recruitment of IL-31+ T cells to neuronal IL31RA+ structures and immuno-neuronal communication could then feed into the severity of itch, inflammation, and changes of the epidermal nerve fiber density characteristic for AD.