Molecular signature of pruriceptive MrgprA3⁺ neurons

Abstract

Itch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3 + sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3 + neurons under both naï ve and allergic contact dermatitis condition.Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3 + neurons, suggesting that MrgprA3 + neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3 + neurons. We also discovered that MrgprA3 + neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

Interactions of the Neuro‒Immune‒Stromal Triad in Itch

“…This model postulated that there are separate or partially discrete receptor sensory neurons that activate separate pain and itch neural pathways. Functional studies in mice uncovered at least two cell populations tuned to detect pruritogens by virtue of the genes they express (Han et al, 2013;Mishra and Hoon, 2013;Solinski et al, 2019b;Xing et al, 2020). One neural subtype selectively expresses natriuretic polypeptide B (NPPB), an itch-specific neuropeptide; the second subtype expresses selectively the itch receptor MRGPRA3 (Han et al, 2013;Liu et al, 2009).…”

Neuropathic Itch

“…In mouse models of allergic contact dermatitis, inflamed skin exhibits nerve hyperproliferation and alters sensory neuron expression profiles. In several inflammatory dermatoses, including psoriasis, systemic sclerosis, morphea, dermatomyositis, and atopic dermatitis, neuropathic-type itch, pain, and other symptoms have been documented [ 24 , 25 , 26 ]. Inflammation increases intraepidermal nerve fiber density.…”

mMrgprA3/mMrgprC11/hMrgprX1: Potential therapeutic targets for allergic contact dermatitis–induced pruritus in mice and humans

“…Itch sensation is initiated by the activation of sensory neurons whose cell bodies reside in the dorsal root ganglion (DRG) or trigeminal ganglion (TG) 5 . Several sensory neuron populations involved in itch detection are identified in recent studies, as well as G‐protein–coupled receptors expressed by these neurons that acutely detect itchy stimuli.…”

“…Ablation of neurons expressing MrgprA3 attenuates dry skin and allergic itch, suggesting that MrgprA3 + neurons are necessary for the development of chronic itch. Therefore, MrgprA3 + sensory neurons are suggested as one of the major itch‐sensing neuronal populations 5 …”

“…Itch sensation is initiated by the activation of sensory neurons whose cell bodies reside in the dorsal root ganglion (DRG) or trigeminal ganglion (TG). 5 Several sensory neuron populations involved in itch detection are identified in recent studies, as well as G-protein-coupled receptors expressed by these neurons that acutely detect itchy stimuli. The best understood of these itch signalling cascades is histaminergic pathway; however, ACDassociated chronic itch is commonly resistant to antihistamines, underscoring the importance and clinical relevance of histamineindependent pruritic receptors.…”