Hemolysis transforms liver macrophages into antiinflammatory erythrophagocytes
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Date
2020-10-01Type
- Journal Article
Citations
Cited 18 times in
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Cited 20 times in
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ETH Bibliography
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Abstract
During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as MarcohiHmoxhiMHC class IIlo erythrophagocytes. This phenotype transformation profoundly mitigated disease expression in a model of an anti-CD40–induced hyperinflammatory syndrome with necrotic hepatitis and in a nonalcoholic steatohepatitis model, representing 2 macrophage-driven sterile inflammatory diseases. We reproduced the antiinflammatory erythrophagocyte transformation in vitro by heme exposure of mouse and human macrophages, yielding a distinctive transcriptional signature that segregated heme-polarized from M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells by sequencing defined the transcription factor NFE2L2/NRF2 as a critical driver of erythrophagocytes, and Nfe2l2/Nrf2 deficiency restored heme-suppressed inflammation. Our findings point to a pathway that regulates macrophage functions to link erythrocyte homeostasis with innate immunity. © 2020 American Society for Clinical Investigation. Show more
Publication status
publishedExternal links
Journal / series
The Journal of Clinical InvestigationVolume
Pages / Article No.
Publisher
American Society for Clinical InvestigationOrganisational unit
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
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Citations
Cited 18 times in
Web of Science
Cited 20 times in
Scopus
ETH Bibliography
yes
Altmetrics