Chronic itch is a complex sensation of the skin frequently associated with
skin diseases, such as
atopic dermatitis (AD) and
psoriasis. Although
Serpin E1 is implicated in chronic itch, its receptor and signaling pathways involved in itch are not known. In this study, the clinical relevance of a putative
Serpin E1 receptor PLAUR to chronic itch, and the neuro-cutaneous
Serpin E1-PLAUR signaling are explored. We found that PLAUR is overexpressed in skin specimens of human lesional AD and lesional
psoriasis, and sensory neurons innervating MC903-induced AD-like murine skin. Murine PLAUR+ sensory neurons responded to
Serpin E1, resulting in enrichment of numerous itch- and
inflammation-related genes and their
protein release. PLAUR resides in TLR2+ neurons and
Serpin E1 stimulus led to transcriptional upregulation of TLR2 and its co-signaling
proteins. Agonists of TLR2 propagated itch-related gene transcription including BNP, OSM, and PAR2. OSM induced acute itch in mice and promoted
G-CSF and
IL-8 release from human keratinocytes.
Serpin E1 inhibitor reduced MC903-induced itch, epidermal
hyperplasia, immunocyte infiltration, and resulted in lower transcription/expression levels of
Serpin E1 and OSM. Taken together, the PLAUR-TLR2-OSM signaling promotes skin-nerve communication, cutaneous
inflammation, and itch, all feeding into an aggravation of AD and exaggerated itch circuits.