Prostaglandin E₂ inhibits neutrophil extracellular trap formation through production of cyclic AMP

Background and Purpose Upon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs), which contain unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defence, although the role of PGE₂, a bioactive substance generated in inflammatory tissues, in the formation of NETs remains unclear. Experimental Approach The effects of PGE₂, agonists and antagonists of its receptors, and modulators of the cAMP-PKA pathway on the formation of NETs were examined in vitro in isolated neutrophils and in vivo in a newly established mouse model. Key Results PGE₂ inhibited PMA-induced NET formation in vitro through EP₂ and EP₄ Gαs-coupled receptors. Incubation with a cell-permeable cAMP analogue, dibutyryl cAMP, or various inhibitors of a cAMP-degrading enzyme, PDE, also suppressed NET formation. In the assay established here, where an agarose gel was s.c. implanted in mice and NET formation was detected on the surface of the gel, the extent of the NET formed was inhibited in agarose gels containing rolipram, a PDE4 inhibitor, and butaprost, an EP₂ receptor agonist. Conclusions and Implications PGE₂ inhibits NET formation through the production of cAMP. These findings will contribute to the development of novel treatments for NETosis-related diseases.