title: Allergic inflammation is augmented via histamine H4 receptor activation: The role of natural killer cells in vitro and in vivo.
abstract: BACKGROUND
  Natural Killer cells (NK cells) are identified as pivotal mediators in allergic skin diseases and accumulate in lesions of atopic dermatitis (AD) patients. Histamine levels are increased in these lesions and histamine is involved in chemotaxis in dendritic cells and NK cells.
  
  
  OBJECTIVE
  The aim of this study was to determine if the histamine H4 receptor (H4R) mediates NK cell chemotaxis and whether it influences interplay between NK cells and dendritic cells during the early phase of allergic inflammation.
  
  
  METHODS
  Chemotactic function of the H4R as well as the influence of the H4R on the cytokine profile of an NK cell-dendritic cell co-culture was studied in vitro. The effect of H4R activation on NK cell migration, NK cell-dendritic cell interaction and cytokine levels in the skin was further characterized in the murine TDI model of allergic dermatitis. Additionally, the impact of the H4R on dermal NK cells was determined in the ovalbumin (OVA)- induced allergic dermatitis model, comparing wild type and H4R knockout mice.
  
  
  RESULTS
  The selective H4R agonist ST-1006 induced NK cell chemotaxis in vitro, which was inhibited with the H4R antagonist JNJ7777120. In vivo, mice treated with TDI plus ST-1006 topically onto the ear, showed significantly enhanced ear swelling and an increased number of NK cells compared to just allergen challenged ears. CCL17 levels in the ear were also significantly increased 8h after allergen challenge. Histology revealed that the main source for increased CCL17 were dendritic cells. These effects could be blocked using the H4R antagonist JNJ7777120. In the chronic model of allergic dermatitis, OVA induced NK cell migration into lesional skin sites. The number of NK cells was lower in OVA-sensitized H4R knockout mice compared to wild type mice.
  
  
  CONCLUSIONS
  These results identify the H4R as a new target controlling NK cell migration and NK cell-dendritic cell interaction in the skin during early allergic inflammation. These results further suggest that blocking the H4R in the skin might be beneficial in diseases like AD.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, NC, USA; Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA. Electronic address: sarah_ehling@ncsu.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ehling
authors.affiliation: University of Veterinary Medicine Hannover, Foundation, Institute of Pharmacology, Toxicology and Pharmacy, Hannover, Germany. Electronic address: kristine.rossbach@tiho-hannover.de.
authors.forename: Kristine
authors.initials: K
authors.lastname: Roßbach
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, NC, USA. Electronic address: stan_dunston@ncsu.edu.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Dunston
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine Universität, Düsseldorf, Germany. Electronic address: stark@hhu.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, NC, USA; Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA. Electronic address: wolfgang_baeumer@ncsu.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bäumer
mesh_terms: D000818:Animals; D054414:Chemokine CCL17 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity
chemical_list: C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; C498829:Hrh4 protein, mouse; D007211:Indoles; C000610568:N4-(2,6-dichlorobenzyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine; D010879:Piperazines; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D014051:Toluene 2,4-Diisocyanate; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D006632:Histamine; D010047:Ovalbumin
keywords: Allergic contact dermatitis; CCL17/TARC; Dermal dendritic cells; Histamine H4 receptor; Natural killer cells