title: TNF-α/TNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms.
abstract: Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha (TNF-α) and its receptors TNF receptor subtype-1 (TNFR1) and TNFR2 in acute and chronic itch in mice. Compared to wild-type (WT) mice, TNFR1-knockout (TNFR1-KO) and TNFR1/R2 double-KO (DKO), but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine (CQ). Application of the TNF-synthesis inhibitor thalidomide and the TNF-α antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia (DRG) and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.
authors.affiliation: The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, 215600, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Miao
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, 215021, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, 215021, China.
authors.forename: Teng-Teng
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, 215021, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Guo
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, 215021, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Capital Medical University Electric Power Teaching Hospital, Beijing, 100073, China.
authors.forename: Xue-Long
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, 215123, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Chen
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, 215021, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.|Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.affiliation: The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, 215600, China. liutong80@suda.edu.cn.|Institute of Neuroscience, Soochow University, Suzhou, 215021, China. liutong80@suda.edu.cn.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D002738:Chloroquine / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068800:Etanercept / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013792:Thalidomide / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D003189:p-Methoxy-N-methylphenethylamine / Q000633:toxicity
chemical_list: D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D003189:p-Methoxy-N-methylphenethylamine; D013792:Thalidomide; D002738:Chloroquine; D000068800:Etanercept
keywords: Central sensitization; Itch; Spinal cord; Tumor necrosis factor; Tumor necrosis factor receptor