Resolution of inflammation increases erythropoiesis

Erythropoiesis is a vital process for blood production, and its disruption contributes to various forms of anemia. In this study, we investigated the hematopoietic effects of bioactive lipid mediators derived from n-3 polyunsaturated fatty acids (n-3 PUFAs), focusing on a class of compounds known as specialized proresolving mediators (SPMs) that promote inflammation resolution. Using zebrafish embryos, we screened several n-3 PUFA-derived SPMs and identified 7(S),17(S)-dihydroxydocosapentaenoic acid (7,17-diHDPAn-3) that significantly enhances erythropoiesis. Exposure to 7,17-diHDPAn-3 upregulated gata1, a key erythroid progenitor marker, and led to increased erythrocyte numbers in both primitive and definitive waves of erythropoiesis. Importantly, the production of platelets, which share a common progenitor with erythrocytes, was unaffected. Metabolomic analysis of sorted erythroid cells, using the transgenic zebrafish line Tg(gata1:DsRed), revealed modest shifts in erythroid cell metabolic profiles. These findings suggest that the erythroid cells produced upon 7,17-diHDPAn-3 exposure, retain a metabolically acceptable profile. In parallel, RNA-sequencing analysis of these cells showed upregulation of hsp90, a heat shock protein gene involved in heme biosynthesis, and downregulation of xpo1b, a gene associated with erythroid maturation. Although we also observed an increase in hematopoietic stem cell-associated genes such as cmyb and runx1, these effects were relatively modest. In combination with dexamethasone, an anti-inflammatory steroid, 7,17-diHDPAn-3 further enhanced the expression of these gene markers, suggesting a potential link between inflammation resolution and early hematopoietic development. Our findings highlight 7,17-diHDPAn-3 as a promising candidate for promoting erythropoiesis and improving red blood cell recovery in vivo, with potential relevance to anemia treatment.