title: Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice.
abstract: BACKGROUND
  Contact toxicant reactions are accompanied by localized skin inflammation and concomitant increases in site-specific itch responses. The role(s) of eosinophils in these reactions is poorly understood. However, previous studies have suggested that localized eosinophil-nerve interactions at sites of inflammation significantly alter tissue innervation.
  
  
  OBJECTIVE
  To define a potential mechanistic link between eosinophils and neurosensory responses in the skin leading to itching.
  
  
  METHODS
  BALB/cJ mice were exposed to different contact toxicants, identifying trimellitic anhydride (TMA) for further study on the basis of inducing a robust eosinophilia accompanied by degranulation. Subsequent studies using TMA were performed with wild type versus eosinophil-deficient PHIL mice, assessing edematous responses and remodeling events such as sensory nerve innervation of the skin and induced pathophysiological responses (ie, itching).
  
  
  RESULTS
  Exposure to TMA, but not dinitrofluorobenzene, resulted in a robust eosinophil skin infiltrate accompanied by significant levels of degranulation. Follow-up studies using TMA with wild type versus eosinophil-deficient PHIL mice showed that the induced edematous responses and histopathology were, in part, causatively linked with the presence of eosinophils. Significantly, these data also demonstrated that eosinophil-mediated events correlated with a significant increase in substance P content of the cutaneous nerves and an accompanying increase in itching, both of which were abolished in the absence of eosinophils.
  
  
  CONCLUSIONS
  Eosinophil-mediated events following TMA contact toxicant reactions increase skin sensory nerve substance P and, in turn, increase itching responses. Thus, eosinophil-nerve interactions provide a potential mechanistic link between eosinophil-mediated events and neurosensory responses following exposure to some contact toxicants.
authors.affiliation: Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz. Electronic address: jjlee@mayo.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Division of Hematology and Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Protheroe
authors.affiliation: Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Huijun
authors.initials: H
authors.lastname: Luo
authors.affiliation: Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Ochkur
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Ore.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Scott
authors.affiliation: Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Zellner
authors.affiliation: Media Support Services, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Raish
authors.affiliation: Department of Dermatology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Dahl
authors.affiliation: Department of Dermatology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Vega
authors.affiliation: Division of Hematology and Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Olivia
authors.initials: O
authors.lastname: Conley
authors.affiliation: Division of Hematology and Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Condjella
authors.affiliation: Brophy College Preparatory, Department of Science, Phoenix, Ariz.
authors.forename: Jake A
authors.initials: JA
authors.lastname: Kloeber
authors.affiliation: Brophy College Preparatory, Department of Science, Phoenix, Ariz.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Neely
authors.affiliation: Brophy College Preparatory, Department of Science, Phoenix, Ariz.
authors.forename: Yash S
authors.initials: YS
authors.lastname: Patel
authors.affiliation: Brophy College Preparatory, Department of Science, Phoenix, Ariz.
authors.forename: Patty
authors.initials: P
authors.lastname: Maizer
authors.affiliation: Brophy College Preparatory, Department of Science, Phoenix, Ariz.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mazzolini
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Ore.
authors.forename: Allison D
authors.initials: AD
authors.lastname: Fryer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Ore.
authors.forename: Noah W
authors.initials: NW
authors.lastname: Jacoby
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Ore.
authors.forename: David B
authors.initials: DB
authors.lastname: Jacoby
authors.affiliation: Division of Hematology and Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, Ariz.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Lee
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D015550:Cell Degranulation; D003094:Collagen / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D005355:Fibrosis; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010796:Phthalic Anhydrides / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D011537:Pruritus / Q000175:diagnosis / Q000209:etiology*; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000294:innervation* / Q000473:pathology; D013373:Substance P / Q000235:genetics / Q000378:metabolism
chemical_list: D000485:Allergens; D010796:Phthalic Anhydrides; D013373:Substance P; C015559:trimellitic anhydride; D003094:Collagen; D004139:Dinitrofluorobenzene
keywords: Contact hypersensitivity; degranulation; eosinophil-deficient; sensory nerve