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.