TY - JOUR
T1 - Sensory neuron-expressed TRPC3 mediates acute and chronic itch
AU - Liu, Yan
AU - Liu, Yutong
AU - Limjunyawong, Nathachit
AU - Narang, Claire
AU - Jamaldeen, Hanna
AU - Yu, Shimeng
AU - Patiram, Shivanie
AU - Nie, Hong
AU - Caterina, Michael J.
AU - Dong, Xinzhong
AU - Qu, Lintao
N1 - Funding Information:
This work was support by a startup (to L. Qu) from Neurosurgery Pain Research Institute and Catalyst Award (to L. Qu) at Johns Hopkins University. Y. T. Liu's effort was partially supported by training scholarships from Jinan University and Lin Jian Biomedicine Development Foundation. The authors thank Drs. Barbara Miller (Pennsylvania State University) and Lutz Birnbaumer (NIEHS) for providing the donor breeders of global Trpc3 knockout and Trpc3 mice, respectively. The authors thank Jonah Kaziyev for behavioral data analysis. The authors also thank Ian Reucroft for mouse colony maintenance. fl/fl
Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.
AB - Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.
KW - Dermatitis
KW - Itch
KW - Pain
KW - Primary sensory neurons
KW - TRPC3
UR - http://www.scopus.com/inward/record.url?scp=85144588783&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144588783&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000002668
DO - 10.1097/j.pain.0000000000002668
M3 - Article
C2 - 35507377
AN - SCOPUS:85144588783
SN - 0304-3959
VL - 164
SP - 98
EP - 110
JO - Pain
JF - Pain
IS - 1
ER -