Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia
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Updated: Aug 24, 2026
In vitro Coculture Assay to Assess Pathogen Induced Neutrophil Trans-epithelial Migration
Published on: January 6, 2014
Randall J Mrsny1, Andrew T Gewirtz, Dario Siccardi
1School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, Wales CF10 3XF, United Kingdom.
Abstract:
The mechanism by which neutrophils [polymorphonuclear leukocyte (PMNs)] are stimulated to move across epithelial barriers at mucosal surfaces has been basically unknown in biology. IL-8 has been shown to stimulate PMNs to leave the bloodstream at a local site of mucosal inflammation, but the chemical gradient used by PMNs to move between adjacent epithelial cells and traverse the tight junction at the apical neck of these mucosal barriers has eluded identification. Our studies not only identify this factor, previously termed pathogen-elicited epithelial chemoattractant, as the eicosanoid hepoxilin A(3) (hepA(3)) but also demonstrate that it is a key factor promoting the final step in PMN recruitment to sites of mucosal inflammation. We show that hepA(3) is synthesized by epithelial cells and secreted from their apical surface in response to conditions that stimulate inflammatory events. Our data further establish that hepA(3) acts to draw PMNs, via the establishment of a gradient across the epithelial tight junction complex. The functional significance of hepA(3) to target PMNs to the lumen of the gut at sites of inflammation was demonstrated by the finding that disruption of the 12-lipoxygenase pathway (required for hepA(3) production) could dramatically reduce PMN-mediated tissue trauma, demonstrating that hepA(3) is a key regulator of mucosal inflammation.
Insights
This study identifies hepoxilin A(3) (hepA(3)) as the key chemoattractant guiding neutrophils across epithelial barriers during mucosal inflammation. Disrupting its production reduces inflammation and tissue damage.
Area of Science:
- Immunology
- Cell Biology
- Gastroenterology
Background:
- Neutrophil (polymorphonuclear leukocyte - PMN) transmigration across epithelial barriers is crucial for mucosal immunity but the underlying mechanisms remain largely unknown.
- Interleukin-8 (IL-8) facilitates PMN exit from circulation during inflammation, yet the specific chemoattractant guiding PMNs through epithelial tight junctions has not been identified.
Purpose of the Study:
- To identify the chemoattractant responsible for the final step of neutrophil recruitment across epithelial barriers at mucosal surfaces.
- To elucidate the role of this chemoattractant in regulating mucosal inflammation and associated tissue damage.
Main Methods:
- Investigated the role of eicosanoids in neutrophil transmigration.
- Analyzed the synthesis and secretion of potential chemoattractants by epithelial cells.
- Examined the effect of disrupting the 12-lipoxygenase pathway on neutrophil recruitment and tissue injury in an inflammatory model.
Main Results:
- Identified hepoxilin A(3) (hepA(3)) as the previously termed pathogen-elicited epithelial chemoattractant.
- Demonstrated that epithelial cells synthesize and secrete hepA(3) apically in response to inflammatory stimuli.
- Showed that hepA(3) establishes a gradient across the epithelial tight junction, attracting PMNs.
- Found that inhibiting hepA(3) production via the 12-lipoxygenase pathway significantly reduced PMN-mediated tissue trauma.
Conclusions:
- Hepoxilin A(3) is a critical regulator of neutrophil recruitment to sites of mucosal inflammation.
- Targeting hepA(3) production offers a potential therapeutic strategy for reducing inflammatory tissue damage in mucosal tissues like the gut.
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