Erythroblast-derived lipid mediators program neutrophil development and function

Abstract

Granulopoiesis is a tightly regulated process encompassing the production, maturation, and release of neutrophils in the bone marrow, ensuring their optimal physiological contribution to host defence. The mechanisms that maintain a balanced regulation of neutrophil effector functions during this process remain incompletely understood. Here, we identify bone marrow-resident erythroblasts as a key source of specialized pro-resolving mediators (SPMs) and show that they imprint neutrophil development and function. Terminally differentiating erythroblasts highly express the key SPM biosynthetic enzyme 12/15-lipoxygenase (Alox15) and accordingly generate several SPMs, including n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA). Conditional erythroblast-specific depletion of Alox15 decreased bone marrow SPM levels and caused altered neutrophil phenotypes, including augmented release of reactive oxygen species and neutrophil extracellular traps, as well as increased migration to chemotactic stimuli. This was accompanied by increased neutrophil sequestration in peripheral organs and concomitant neutropenia. Mice with erythroblast-specific Alox15 depletion displayed impaired bacterial clearance in experimental peritonitis and increased severity in DSS-colitis. Aberrant neutrophil phenotypes were rectified by the reconstitution of RvD5n-3 DPA and were largely recapitulated by the specific depletion of the SPM receptor Gpr101 in bone marrow macrophages, but not in neutrophil precursors, suggesting involvement of the macrophage niche in mediating the SPM effects on granulopoiesis. Our findings establish a central role for erythroblasts and their SPM production in instructing granulopoiesis for balanced functional neutrophil responses.