RRC ID 69170
Author Vallelian F, Buzzi RM, Pfefferlé M, Yalamanoglu A, Dubach IL, Wassmer A, Gentinetta T, Hansen K, Humar R, Schulthess N, Schaer CA, Schaer DJ.
Title Heme-stress activated NRF2 skews fate trajectories of bone marrow cells from dendritic cells towards red pulp-like macrophages in hemolytic anemia.
Journal Cell Death Differ
Abstract Heme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias, such as sickle cell disease. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Since chronic heme-stress is noxious for macrophages, erythrophagocytes in the spleen are continuously replenished from bone marrow-derived progenitors. Here, we hypothesized that adaptation to heme stress progressively shifts differentiation trajectories of bone marrow progenitors to expand the capacity of heme-handling monocyte-derived macrophages at the expense of the homeostatic generation of dendritic cells, which emerge from shared myeloid precursors. This heme-induced redirection of differentiation trajectories may contribute to hemolysis-induced secondary immunodeficiency. We performed single-cell RNA-sequencing with directional RNA velocity analysis of GM-CSF-supplemented mouse bone marrow cultures to assess myeloid differentiation under heme stress. We found that heme-activated NRF2 signaling shifted the differentiation of bone marrow cells towards antioxidant, iron-recycling macrophages, suppressing the generation of dendritic cells in heme-exposed bone marrow cultures. Heme eliminated the capacity of GM-CSF-supplemented bone marrow cultures to activate antigen-specific CD4 T cells. The generation of functionally competent dendritic cells was restored by NRF2 loss. The heme-induced phenotype of macrophage expansion with concurrent dendritic cell depletion was reproduced in hemolytic mice with sickle cell disease and spherocytosis and associated with reduced dendritic cell functions in the spleen. Our data provide a novel mechanistic underpinning of hemolytic stress as a driver of hyposplenism-related secondary immunodeficiency.
Volume 29(8)
Pages 1450-1465
Published 2022-8-1
DOI 10.1038/s41418-022-00932-1
PII 10.1038/s41418-022-00932-1
PMID 35031770
PMC PMC9345992
MeSH Anemia, Sickle Cell* Animals Bone Marrow Cells* / cytology Cell Differentiation Dendritic Cells* / cytology Erythropoiesis Granulocyte-Macrophage Colony-Stimulating Factor Heme* Hemolysis Iron Macrophages* / cytology Mice Mice, Inbred C57BL NF-E2-Related Factor 2* / metabolism RNA Spleen
IF 10.717
Mice RBRC09595