Inhibition of allergen-induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non-human primates

Br J Pharmacol. 2020 Jan;177(2):360-371. doi: 10.1111/bph.14872. Epub 2020 Jan 17.


Background and purpose: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys.

Experimental approach: In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first-generation" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM.

Key results: In a pilot experiment, both 5-oxo-ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230. Subsequently, we found that the related OXE antagonist S-Y048 is a highly potent inhibitor of 5-oxo-ETE-induced activation of rhesus monkey eosinophils in vitro and has a half-life in plasma of about 6 hr after oral administration. S-Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5-oxo-ETE and HDM.

Conclusions and implications: 5-Oxo-ETE may play an important role in allergen-induced eosinophilia. Blocking its effects with S-Y048 may provide a novel therapeutic approach for eosinophilic diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allergens*
  • Animals
  • Anti-Allergic Agents / chemical synthesis
  • Anti-Allergic Agents / pharmacokinetics
  • Anti-Allergic Agents / pharmacology*
  • Antigens, Helminth / immunology
  • Arachidonic Acids
  • Ascaris suum / immunology
  • Cells, Cultured
  • Chemotaxis, Leukocyte / drug effects*
  • Dermatitis / immunology
  • Dermatitis / metabolism
  • Dermatitis / prevention & control*
  • Disease Models, Animal
  • Eosinophilia / immunology
  • Eosinophilia / metabolism
  • Eosinophilia / prevention & control*
  • Eosinophils / drug effects*
  • Eosinophils / immunology
  • Eosinophils / metabolism
  • Insect Proteins / immunology
  • Macaca fascicularis
  • Macaca mulatta
  • Male
  • Pilot Projects
  • Pyroglyphidae / immunology
  • Receptors, Eicosanoid / antagonists & inhibitors*
  • Receptors, Eicosanoid / metabolism
  • Signal Transduction
  • Skin / drug effects*
  • Skin / immunology
  • Skin / metabolism


  • 5-oxo-eicosatetraenoic acid
  • Allergens
  • Anti-Allergic Agents
  • Antigens, Helminth
  • Arachidonic Acids
  • Insect Proteins
  • Receptors, Eicosanoid