Involvement of Neuro-Immune Interactions in Pruritus With Special Focus on Receptor Expressions

Abstract

Pruritus is a common, but very challenging symptom with a wide diversity of underlying causes like dermatological, systemic, neurological and psychiatric diseases. In dermatology, pruritus is the most frequent symptom both in its acute and chronic form (over 6 weeks in duration). Treatment of chronic pruritus often remains challenging. Affected patients who suffer from moderate to severe pruritus have a significantly reduced quality of life. The underlying physiology of pruritus is very complex, involving a diverse network of components in the skin including resident cells such as keratinocytes and sensory neurons as well as transiently infiltrating cells such as certain immune cells. Previous research has established that there is a significant crosstalk among the stratum corneum, nerve fibers and various immune cells, such as keratinocytes, T cells, basophils, eosinophils and mast cells. In this regard, interactions between receptors on cutaneous and spinal neurons or on different immune cells play an important role in the processing of signals which are important for the transmission of pruritus. In this review, we discuss the role of various receptors involved in pruritus and inflammation, such as TRPV1 and TRPA1, IL-31RA and OSMR, TSLPR, PAR-2, NK1R, H1R and H4R, MRGPRs as well as TrkA, with a focus on interaction between nerve fibers and different immune cells. Emerging evidence shows that neuro-immune interactions play a pivotal role in mediating pruritus-associated inflammatory skin diseases such as atopic dermatitis, psoriasis or chronic spontaneous urticaria. Targeting these bidirectional neuro-immune interactions and the involved pruritus-specific receptors is likely to contribute to novel insights into the underlying pathogenesis and targeted treatment options of pruritus.

One Size Does Not Fit All: Diversifying Immune Function in the Skin

“…Indeed, skin innervating nerve fibers robustly express receptors for a number of cytokines, including the IL-4 receptor, and remarkably, inhibiting JAK1 signaling downstream of the IL-4 receptor antagonist dramatically improves clinical pruritis (50). The neuroimmune axis is pathologically co-opted pruritis (itch)associated inflammatory diseases, such as atopic dermatitis, psoriasis, and chronic spontaneous urticaria (51). Just as immune stimuli provoke neurons, sensory neurons similarly drive inflammation.…”

Further Understanding of Neuro-Immune Interactions in Allergy: Implications in Pathophysiology and Role in Disease Progression

“… 153 In addition to the intense biochemical crosstalk between immune cells and neurons, the interactions within the neuro-immune system also derive from sharing many properties, such as receptor and ligand expression, that enable efficient communication between the two systems. 7 , 156 …”

Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation

“…IL-31, which belongs to the IL-6 family of cytokines, is produced by Th2 cells, mast cells, eosinophils, basophils, macrophages and DCs [19,89,[107][108][109][110][111]. IL-31 binds to its receptor, a complex composed of IL-31 receptor A (IL-31RA) and oncostatin M (OSM) receptor, which is expressed on keratinocytes, epithelial cells, mast cells, basophils, eosinophils, macrophages, sensory neurons, DRG and the dorsal horn of the spinal cord [13,89,91,111].…”

“…Thymic stromal lymphopoietin (TSLP) is a IL-7 like cytokine belonging to the IL-2 cytokine family [110,141]. It is primarily produced by epithelial cells, including keratinocytes, fibroblasts and stromal cells, as well as by DCs, mast cells, and basophils [110,142].…”

“…Thymic stromal lymphopoietin (TSLP) is a IL-7 like cytokine belonging to the IL-2 cytokine family [110,141]. It is primarily produced by epithelial cells, including keratinocytes, fibroblasts and stromal cells, as well as by DCs, mast cells, and basophils [110,142]. Its receptor, TSLPR, is expressed on monocytes/macrophages, T cells, B cells, mast cells, eosinophils, NK cells, DCs, keratinocytes and sensory neuronal endings [143][144][145][146][147][148].…”