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dc.contributor.author
Pfefferlé, Marc
dc.contributor.author
Ingoglia, Giada
dc.contributor.author
Schär, Christian A.
dc.contributor.author
Yalamanoglu, Ayla
dc.contributor.author
Buzzi, Raphael
dc.contributor.author
Dubach, Irina L.
dc.contributor.author
Tan, Ge
dc.contributor.author
López-Cano, Emilio Y.
dc.contributor.author
Schulthess, Nadja
dc.contributor.author
Hansen, Kerstin
dc.contributor.author
Humar, Rok
dc.contributor.author
Schaer, Dominik J.
dc.contributor.author
Vallelian, Florence
dc.date.accessioned
2020-10-19T09:52:57Z
dc.date.available
2020-10-16T03:41:06Z
dc.date.available
2020-10-19T09:52:57Z
dc.date.issued
2020-10-01
dc.identifier.issn
1558-8238
dc.identifier.issn
0021-9738
dc.identifier.other
10.1172/JCI137282
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/446227
dc.description.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.
en_US
dc.language.iso
en
en_US
dc.publisher
American Society for Clinical Investigation
en_US
dc.title
Hemolysis transforms liver macrophages into antiinflammatory erythrophagocytes
en_US
dc.type
Journal Article
dc.date.published
2020-07-14
ethz.journal.title
The Journal of Clinical Investigation
ethz.journal.volume
130
en_US
ethz.journal.issue
10
en_US
ethz.journal.abbreviated
J Clin Invest
ethz.pages.start
5576
en_US
ethz.pages.end
5590
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Ann Arbor, MI
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung / Domain VP Research::02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung / Domain VP Research::02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
ethz.date.deposited
2020-10-16T03:41:12Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2020-10-19T09:53:11Z
ethz.rosetta.lastUpdated
2022-03-29T03:36:45Z
ethz.rosetta.versionExported
true
ethz.COinS
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