Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 15% to 20% of the general population in developed countries.¹ It is characterized by recurrent eczematous legions and intense itch. Because the itch sensation induces scratching behavior, which exacerbates the skin inflammation and disturbs the quality of life of affected individuals, chronic itch is a challenging clinical problem in the treatment of AD.

Itch can be induced by various chemical mediators. Among them, much attention has been paid to IL-31 as an AD-associated itch mediator since the discovery of the pruritogenic action of IL-31 in mice.² IL-31 is mainly produced by CD4⁺ T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor (OSMR), both of which are expressed in various cell types including dorsal root ganglion (DRG) neurons.³ A recent clinical study has demonstrated that blockade of IL-31 signals by a specific antibody for IL-31 receptor A alleviates pruritus in patients with AD.⁴ However, the neuronal mechanism underlying IL-31–induced itch sensation is poorly understood.

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch

Abstract

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupledreceptor(Mrgpr)familyhavebeen identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itchsensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus

Babina Sanjel,^1,2Han-Joo Maeng,^1,2 and  Won-Sik Shim^1,2

Abstract

Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.

Subject terms: Sensory processing, Molecular neuroscience