Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy

Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy

Background Food allergy, in particular peanut allergy, is a growing concern in Western countries. The prevalence of allergy to peanut, which currently stands at 1.4%, nearly tripled between 1997 and 2008. Allergic sensitization is a particularly difficult process to study as it is clinically silent....

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Published in:Allergy (Copenhagen) Vol. 70; no. 5; pp. 495 - 505
Main Authors: Kong, J., Chalcraft, K., Mandur, T. S., Jimenez‐Saiz, R., Walker, T. D., Goncharova, S., Gordon, M. E., Naji, L., Flader, K., Larché, M., Chu, D. K., Waserman, S., McCarry, B., Jordana, M.
Format: Journal Article
Language:English
Published: Denmark Blackwell Publishing Ltd 01-05-2015
Subjects:
Acids
Alarmins - immunology
Alarmins - metabolism
allergic sensitization
Animals
Arachis hypogaea
danger‐associated molecular pattern
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Food allergies
Humans
Immunoglobulin E - blood
Immunoglobulin E - immunology
Immunoglobulin G - blood
Immunoglobulin G - immunology
Metabolism
Metabolomics
Mice
Mice, Inbred C57BL
peanut allergy
Peanut Hypersensitivity - immunology
Peanut Hypersensitivity - metabolism
Peanuts
uric acid
Uric Acid - immunology
Uric Acid - metabolism
peanut allergy
metabolomics
uric acid
allergic sensitization
danger-associated molecular pattern
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Summary:Background Food allergy, in particular peanut allergy, is a growing concern in Western countries. The prevalence of allergy to peanut, which currently stands at 1.4%, nearly tripled between 1997 and 2008. Allergic sensitization is a particularly difficult process to study as it is clinically silent. We sought to identify key pathways and mediators critically involved in the induction of allergic sensitization to peanut. Methods Comprehensive metabolomics analysis with liquid chromatography–mass spectrometry was used to detect metabolite changes in mice (C57BL/6) undergoing sensitization. Loss‐of‐function and gain‐of‐function studies were performed in mice subjected to two models of peanut sensitization and anaphylaxis that involved either oral or epicutaneous sensitization. Flow cytometric analyses on dendritic cells (DCs) in vitro and in vivo were used to investigate the mechanisms of immune activation. Results Elevated levels of uric acid (UA) were detected in mice undergoing sensitization as well as in peanut‐allergic children who were not challenged with peanut. In mice, the depletion of UA during sensitization prevented the development of peanut‐specific immunoglobulins IgE and IgG1 as well as anaphylaxis while exogenous delivery of UA crystals (monosodium urate, MSU) restored the allergic phenotype. Monosodium urate enhanced CD86 and OX40L expression on DCs, independent of Toll‐like receptors 2 and 4, the NLRP3 inflammasome, and IL‐1β, via a PI3K signaling pathway. Conclusion Overproduction of the UA alarmin in the local microenvironment plays a critical role in the induction of peanut‐allergic sensitization, likely due to its ability to activate DCs. These finding suggest that cellular damage or tissue injury may be an essential requisite for the development of allergic sensitization to foods.
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ISSN:0105-4538
1398-9995
DOI:10.1111/all.12579