title: Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology and Molecular Medicine and McMaster Immunology Research Centre (MIRC), McMaster University, Hamilton, ON, Canada.
authors: J
authors: J
authors: Kong
authors: K
authors: K
authors: Chalcraft
authors: T S
authors: TS
authors: Mandur
authors: R
authors: R
authors: Jimenez-Saiz
authors: T D
authors: TD
authors: Walker
authors: S
authors: S
authors: Goncharova
authors: M E
authors: ME
authors: Gordon
authors: L
authors: L
authors: Naji
authors: K
authors: K
authors: Flader
authors: M
authors: M
authors: Larché
authors: D K
authors: DK
authors: Chu
authors: S
authors: S
authors: Waserman
authors: B
authors: B
authors: McCarry
authors: M
authors: M
authors: Jordana
mesh_terms: D000067531:Alarmins / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D021183:Peanut Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D014527:Uric Acid / Q000276:immunology* / Q000378:metabolism
chemical_list: D000067531:Alarmins; D007074:Immunoglobulin G; D014527:Uric Acid; D007073:Immunoglobulin E
keywords: allergic sensitization; danger-associated molecular pattern; metabolomics; peanut allergy; uric acid