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Status |
Public on Aug 13, 2020 |
Title |
Erythrophagocytosis drives anti-inflammatory programming of liver macrophages (ATAC-seq) |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Under conditions of erythrolytic stress, which accompanies many disease states, macrophages play key roles in phagocytosing damaged RBCs and preventing the toxic effects of cell-free hemoglobin and heme to maintain homeostasis. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we show that erythrolytic stress promotes expansion of a specific macrophage population in the liver (which we named “erythrophagocytes”) expressing high levels of Marco and Hmox1 and low levels of MHC class II related genes with an anti-inflammatory gene expression signature. We confirmed the strong anti-inflammatory function of erythrophagocytes in two models of sterile inflammatory liver disease: anti-CD40 antibody-induced systemic inflammation syndrome with necrotizing hepatitis and diet-induced nonalcoholic fatty liver disease (NAFLD). The unique anti-inflammatory phenotype and function of erythrophagocytes was reproduced in vitro by heme-exposure of mouse macrophages, yielding a transcriptional profile that segregated heme-polarized from classical M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells using sequencing (scATAC-seq) suggested NFE2L2/NRF2 as a critical driver of anti-inflammatory erythrophagocytes in the livers of hemolytic mice and heme-suppression of the inflammatory response was abolished in macrophages from Nfe2l2/Nrf2-deficient animals. Our findings point to a novel pathway that regulates macrophage functions to link RBC homeostasis and heme metabolism with innate immunity.
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Overall design |
Liver macrophages from a sph/sph mouse and its littermate wild-type control were isolated using anti-F4/80 antibody coated dynabeads and subjected to droplet-based single-cell ATAC(10x genomics).
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Contributor(s) |
Pfefferlé M, Ingoglia G, Vallelian F, Schaer D |
Citation(s) |
32663195 |
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Submission date |
May 28, 2020 |
Last update date |
Nov 27, 2020 |
Contact name |
Marc Pfefferle |
E-mail(s) |
marc.pfefferle@uzh.ch
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Organization name |
University hospital Zürich (USZ)
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Street address |
Wagistrasse 12
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City |
Schlieren |
State/province |
Schweiz |
ZIP/Postal code |
8952 |
Country |
Switzerland |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (2) |
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This SubSeries is part of SuperSeries: |
GSE145244 |
Erythrophagocytosis drives anti-inflammatory programming of liver macrophages |
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Relations |
BioProject |
PRJNA635691 |
SRA |
SRP265162 |