Itch is a primary symptom of many allergic conditions, and severely affects the quality of life and productivity. Primary sensory neurons residing in the trigeminal ganglia and dorsal root ganglia (DRG) play an essential role in the generation of allergic itch. These neurons detect endogenous itch-inducing molecules (pruritogens) via a group of itch receptors on their peripheral axons in the skin or mucosal membrane tissues, and transmit signals to the spinal cord via their central axons. In contrast to the well-studied histamine pathway, histamine-independent itch pathways in allergic itch remain poorly defined. Previously, we identified several novel itch receptors within a large family of G-protein?coupled receptors called Mrgprs. We found that several Mrgprs recognize distinct pruritogens, and mediate histamine-independent itch. Our latest results indicate that Mrgprs are required for mast cell-mediated allergic itch. This proposal aims to uncover the underlying mechanisms. We will test whether Mrgprs mediate the interaction between mast cells and primary sensory fibers in allergic itch using molecular, genetic and imaging approaches in Aim 1. Furthermore, we will identify the endogenous Mrgpr ligands released by mast cells upon degranulation in Aim 2.
In Aim 3, we seek to translate our discoveries from mice to humans. Human Mrgprs do not form clear orthologous pairs with mouse Mrgprs. Their role in itch is therefore unclear. Based on our preliminary data, we hypothesize that human MrgprX1 mediates neuronal and behavioral response to mast cell-mediated allergy, which will be tested in Aim 3. These studies will reveal the neural basis underlying allergic itch and will have a significant impact on both the study of itch pathogenesis and the clinical treatment of itch.

Public Health Relevance

Despite the clinical importance, the histamine-independent mechanisms of allergic itch remain unknown due to a lack of knowledge about principal pruritogens and itch receptors. This proposal will characterize the role of Mrgprs, a family of histamine-independent itch receptors, in mast cell-mediated allergic itch. These studies will not only advance our understanding of allergic itch at the molecular level, but will also provide a group of new targets for itch management.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Dong, Gang
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Washington University
Schools of Medicine
Saint Louis
United States
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Huang, Cheng-Chiu; Yang, Weishan; Guo, Changxiong et al. (2018) Anatomical and functional dichotomy of ocular itch and pain. Nat Med 24:1268-1276
Espino, Samuel S; Robinson, Samuel D; Safavi-Hemami, Helena et al. (2018) Conopeptides promote itch through human itch receptor hMgprX1. Toxicon 154:28-34
Luo, Jialie; Feng, Jing; Yu, Guang et al. (2018) Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch. J Allergy Clin Immunol 141:608-619.e7
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