Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 2; pp. 477 - 487.e1
• Main Authors: Lee, James J., PhD, Protheroe, Cheryl A., BA, Luo, Huijun, PhD, Ochkur, Sergei I., PhD, Scott, Gregory D., BS, Zellner, Katie R., MS, Raish, Randall J., MS, Dahl, Mark V., MD, Vega, Miriam L., MD, MPH, Conley, Olivia, Condjella, Rachel M., PhD, Kloeber, Jake A, Neely, Joseph L, Patel, Yash S, Maizer, Patty, MS, Mazzolini, Andrew, MA, Fryer, Allison D., PhD, Jacoby, Noah W, Jacoby, David B., MD, Lee, Nancy A., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015; Elsevier Limited
• Subjects: Allergens - administration & dosage; Allergens - immunology; Allergies; Allergy and Immunology; Animals; Biopsy; Cell Degranulation; Collagen; Collagen - metabolism; Contact hypersensitivity; degranulation; Dermatitis; Dinitrofluorobenzene - administration & dosage; Dinitrofluorobenzene - adverse effects; Disease Models, Animal; eosinophil-deficient; Eosinophilia - immunology; Eosinophilia - metabolism; Eosinophilia - pathology; Eosinophils - immunology; Eosinophils - metabolism; Fibrosis; Histology; Histopathology; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Laboratories; Mice; Phthalic Anhydrides - administration & dosage; Phthalic Anhydrides - adverse effects; Phthalic Anhydrides - immunology; Pruritus - diagnosis; Pruritus - etiology; Rodents; sensory nerve; Skin - drug effects; Skin - immunology; Skin - innervation; Skin - pathology; Studies; Substance P - genetics; Substance P - metabolism; Eosinophil activity index; DNFB; Eosinophil peroxidase-specific monoclonal antibody; PGP 9.5; DNCB; TMA; Dinitrofluorobenzene; Dinitrochlorobenzene; EAI; eosinophil-deficient; EPX-mAb; sensory nerve; Pan-neuronal antibody maker; degranulation; Eosinophil-deficient transgenic mice; Trimellitic anhydride (TMA); PHIL; Contact hypersensitivity
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2014.07.003

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.