title: TLR4 enhances histamine-mediated pruritus by potentiating TRPV1 activity.
abstract: BACKGROUND
  Recent studies have indicated that Toll-like receptor 4 (TLR4), a pathogen-recognition receptor that triggers inflammatory signals in innate immune cells, is also expressed on sensory neurons, implicating its putative role in sensory signal transmission. However, the possible function of sensory neuron TLR4 has not yet been formally addressed. In this regard, we investigated the role of TLR4 in itch signal transmission.
  
  
  RESULTS
  TLR4 was expressed on a subpopulation of dorsal root ganglia (DRG) sensory neurons that express TRPV1. In TLR4-knockout mice, histamine-induced itch responses were compromised while TLR4 activation by LPS did not directly elicit an itch response. Histamine-induced intracellular calcium signals and inward currents were comparably reduced in TLR4-deficient sensory neurons. Reduced histamine sensitivity in the TLR4-deficient neurons was accompanied by a decrease in TRPV1 activity. Heterologous expression experiments in HEK293T cells indicated that TLR4 expression enhanced capsaicin-induced intracellular calcium signals and inward currents.
  
  
  CONCLUSIONS
  Our data show that TLR4 on sensory neurons enhances histamine-induced itch signal transduction by potentiating TRPV1 activity. The results suggest that TLR4 could be a novel target for the treatment of enhanced itch sensation.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Min
authors.forename: Hyunkyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Hyoungsub
authors.initials: H
authors.lastname: Lim
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Jang
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Chung
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Korea. sjlee87@snu.ac.kr.
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D057809:HEK293 Cells; D006632:Histamine; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011537:Pruritus / Q000378:metabolism* / Q000473:pathology*; D011968:Receptors, Histamine / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D011968:Receptors, Histamine; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006632:Histamine; D002738:Chloroquine; D002211:Capsaicin; D002118:Calcium