Professional phagocytic granulocyte-derived PGD2 regulates the resolution of inflammation in fish

• Seabream has two orthologs for the mammalian lipocalin-PGDS (PGDS1 and PGDS2).
• PGDS1 is upregulated in acidophilic granulocytes after in vitro activation.
• Acidophilic granulocytes have the ability to release PGD2 upon PAMP stimulation.
• PGD2 and its cyclopentenone derivates modulate the main functional activities of AGs.

Prostaglandins (PGs) play a key role in the development on the immune response through the regulation of both pro- and anti-inflammatory processes. PGD2 can be either pro- or anti-inflammatory depending on the inflammatory milieu. Prostaglandin D synthase (PGDS) is the enzyme responsible for the conversion of PGH2 to PGD2. In mammals, two types of PGDS synthase have been described, the hematopoietic (H-PGDS) and the lipocalin (L-PGDS). In the present study we describe the existence of two orthologs of the mammalian L-PGDS (PGDS1 and PGDS2) in the gilthead seabream and characterize their gene expression profiles and biological activity. The results showed a dramatic induction of the gene coding for PGDS1 in acidophilic granulocytes (AGs), which are functionally equivalent to mammalian neutrophils, after a prolonged in vitro activation with different pathogen associated molecular patterns (PAMPs). In contrast PGDS2 was not expressed in these cells. The functional relevance of the induction of PGDS1 in AGs was confirmed by the ability of these cells to release PGD2 upon PAMP stimulation. To gain further insight into the role of PGD2 in the resolution of inflammation in fish, we examined the ability of PGD2 or its cyclopentenone derivates (cyPGs) to modulate the main functional activities of AGs. It was found that both PGD2 and cyPGs inhibited the production of reactive oxygen species and downregulated the transcript levels of the gene encoding interleukin-1β. Taken together, these results demonstrate that the use of PGD2 and its metabolites in the resolution of inflammation was established before the divergence of fish from tetrapods more than 450 million years ago and support a critical role for granulocytes in the resolution of inflammation in vertebrates.