Mrgprs activation is required for chronic itch conditions in mice

Abstract

Introduction Chronic itch has been drawing much attention due to its clinical significance and the complexity of its mechanisms. To facilitate the development of anti-itch strategies, it is necessary to investigate the key players in itch sensation under chronic itch conditions. Several members of the Mrgpr family were identified as itch receptors that detect cutaneous pruritogens in primary sensory neurons. However, the role of Mrgprs in chronic itch conditions has not been well described. Methods Scratching behaviors of WT and Mrgpr-clusterΔ−/− mice were examined in dry skin model and contact dermatitis model to examine the role of Mrgpr genes in mediating chronic itch sensation. Scratching behaviors of the mice were also examined in allergic itch model. Real-time PCR were performed to examine the expression level of MrgprA3 and MrgprC11 under naïve and dry skin conditions. The MrgprA3+ itch-sensing fibers were labeled by tdTomato fluorescence in Mrgpra3GFP-Cre; ROSA26tdTomato mice, and the morphology and density of those fibers in the epidermis were analyzed under dry skin condition. Results We showed that deleting a cluster of Mrgpr genes in mice reduced scratching behavior severely under two chronic itch conditions, namely dry skin and contact dermatitis, and the allergic itch condition. Moreover, the gene expressions of itch receptors MrgprA3 and MrgprC11 in dorsal root ganglia (DRG) were upregulated significantly under dry skin condition. Consistently, the percentage of MrgprA3+ itch-sensing neurons was increased as well. We also observed hyperinnervation of MrgprA3+ itch-sensing fibers in the epidermis of the skin under dry skin condition. Discussion We demonstrate that Mrgprs play important roles in mediating chronic itch and allergic itch. These findings enrich our knowledge of itch mechanism and may lead to the development of novel therapeutic approach to combat itch.

S1PR3 mediates itch and pain via distinct TRP channel-dependent pathways

“…The complete overlap of S1P-273 responsive neurons with TRPV1 + neurons is consistent with a role for S1P in itch and pain. Previous 274 studies have shown that the MrgprA3+ subpopulation of TRPA1 + neurons is required for many forms of Zhu et al, 2017). In keeping with our hypothesized role for S1P in itch, 80% of 277 chloroquine-responsive MrgprA3 + neurons responded to S1P (Fig.…”

S1PR3 Mediates Itch and Pain via Distinct TRP Channel-Dependent Pathways

“…Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid associated with a variety of skin disorders, including psoriasis (Checa et al, 2015;Myśliwiec et al, 2016), atopic/allergic contact dermatitis (Kohno et al, 2004;Sugita et al, 2010), and scleroderma (Castelino and Varga, 2014), as well as neuropathic pain (Patti et al, 2012;Janes et al, 2014) and other inflammatory diseases (Rivera et al, 2008;Chiba et al, 2010;Tränkner et al, 2014;Donoviel et al, 2015;Roviezzo et al, 2015). S1P signaling via S1P receptor 1 (S1PR1) facilitates the migration, recruitment, and activation of immune cells (Matloubian et al, 2004;Cyster and Schwab, 2012).…”

“…There is evidence supporting both protective and pathogenic effects of S1P signaling in mouse and human chronic itch and inflammatory diseases. In humans, elevated serum S1P is correlated with disease severity in both psoriasis and systemic sclerosis (Castelino and Varga, 2014;Checa et al, 2015;Thieme et al, 2017). Furthermore, ponesimod, an S1PR modulator and blocker of S1P signaling, appears to be promising for psoriasis treatment in humans (Brossard et al, 2013;Vaclavkova et al, 2014;Krause et al, 2018).…”

“…In contrast, in the imiquimod mouse model of psoriasis, it was observed that topical S1P exerts protective effects (Schaper et al, 2013) and, in dogs with atopic dermatitis, it was found that S1P levels are decreased in lesional skin . However, in genetic and chemical mouse models of dermatitis, the S1PR modulator fingolimod, which downregulates the activity of S1PR1, S1PR3, S1PR4, and S1PR5, was found to attenuate inflammation (Kohno et al, 2004;Sugita et al, 2010). In light of these studies, we investigated whether S1P can act as an acute pruritogen in mice.…”

Molecular signature of pruriceptive MrgprA3+ neurons

“…Indeed, ample evidence has demonstrated that nerve injury and inflammation can induce dysregulation of ion channel expression, which results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain (Waxman and Zamponi, 2014). This notion is further supported by the morphological and physiological changes of itch-sensing neurons under chronic itch conditions (Akiyama et al, 2010;Qu et al, 2014;Valtcheva et al, 2015;Zhu et al, 2017). For example, our recent studies demonstrated that NP2 MrgprA3 + neurons exhibit elevated itch receptor expression and hyperinnervation in the skin in a mouse dry skin model (Zhu et al, 2017) and enhanced excitability and spontaneous activities in a contact dermatitis model (Qu et al, 2014).…”