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HOME SCIENCE VOL. 384, NO. 6691 APOPTOTIC CELL IDENTITY INDUCES DISTINCT FUNCTIONAL RESPONSES TO IL-4 IN EFFEROCYTIC MACROPHAGES
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Editor’s summary
Macrophages engulf and remove dying cells within tissues during infection and homeostasis. Liebold
et al. found that macrophages exposed to dying cells in vitro induced different gene expression pro-
grams in response to interleukin-4 depending on the identity of the apoptotic cells that they had en-
gulfed. The same gene expression programs were detected in macrophages from the livers of mice in-
fected with the blood fluke Schistosoma mansoni. Engulfment of apoptotic neutrophils, which was de-
pendent on two phagocytic receptors, augmented a tissue-remodeling profile in macrophages.
Macrophages that were conditioned with both interleukin-4 and apoptotic neutrophils in vitro and
then transferred into mice were protective against S. mansoni infection. —Sarah H. Ross
Structured Abstract
INTRODUCTION
Macrophages acquire specific signatures and functions on the basis of the local tissue signals that
they encounter. Within each tissue, macrophages are constantly exposed to a vast assortment of dy-
ing cells that need to be cleared to maintain homeostasis. So far, the fact that distinct cell lineages
undergo apoptosis, thereby potentially imparting diverse signals to the surrounding environment,
has been overlooked. Specifically, it is not yet clear whether the sensing of apoptotic cells derived
from different cell lineages may differentially influence macrophage activation and contribute to
macrophage functional diversification.
RATIONALE
RESULTS
myeloid cells isolated from S. mansoni–infected mice. The adoptive transfer of macrophages repro-
grammed in vitro through exposure to apoptotic neutrophils—but not other apoptotic cells—amelio-
rated the outcome of S. mansoni infection. The ability of macrophages to take up apoptotic cells is de-
pendent on the engagement of phagocytic receptors. We identified that distinct phagocytic receptors
were required for macrophages to be able to engulf specific types of apoptotic cells. Signaling by way
of these receptors, therefore, could be a potential mechanism regulating the acquisition of different
gene expression signatures in macrophages. We found that the phagocytic receptors AXL and MERTK
were required for the uptake of apoptotic neutrophils and T cells but not hepatocytes. Accordingly,
AXL- and MERTK-dependent phagocytosis controlled the host response to S. mansoni infection, over-
all contributing to parasitic egg clearance.
CONCLUSION
We have identified that the cellular identity of the ingested apoptotic cell contributes to macrophage
gene expression and function. This emphasizes that the identity of apoptotic cells within a tissue en-
vironment may serve as an additional trigger of macrophage functional diversity. Furthermore, our
findings highlight the potential of selective macrophage feeding as an approach to enhance the effec-
tiveness of macrophage-based cell therapies.
The identity of the apoptotic cell sensed is a critical determinant of macrophage functional diversification.
In IL-4–enriched environments, both in vitro and in vivo, macrophages acquire distinct transcriptional signatures and func-
tional phenotypes on the basis of the identity of the apoptotic cell phagocytosed. The engagement of the phagocytic recep-
tors AXL and MERTK contributes to the ability of macrophages to engulf apoptotic neutrophils and, to a lesser extent, apop-
totic T cells and therefore to the acquisition of distinct macrophage profiles. AXL and MERTK do not contribute to the ability
of macrophages to phagocytose apoptotic hepatocytes. PtdSer, phosphatidylserine. ILLUSTRATION: CATERINA DI PIETRO,
VISUALSCISKETCH
Abstract
Macrophages are functionally heterogeneous cells essential for apoptotic cell clearance. Apoptotic
cells are defined by homogeneous characteristics, ignoring their original cell lineage identity. We
found that in an interleukin-4 (IL-4)–enriched environment, the sensing of apoptotic neutrophils by
macrophages triggered their tissue remodeling signature. Engulfment of apoptotic hepatocytes pro-
moted a tolerogenic phenotype, whereas phagocytosis of T cells had little effect on IL-4–induced
gene expression. In a mouse model of parasite-induced pathology, the transfer of macrophages con-
ditioned with IL-4 and apoptotic neutrophils promoted parasitic egg clearance. Knockout of phago-
https://www.science.org/doi/10.1126/science.abo7027 2/6
7/4/24, 16:20 Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages | Science
cytic receptors required for the uptake of apoptotic neutrophils and partially T cells, but not hepato-
cytes, exacerbated helminth infection. These findings suggest that the identity of apoptotic cells may
contribute to the development of distinct IL-4–driven immune programs in macrophages.
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Supplementary Materials
Figs. S1 to S17
Tables S1 to S3
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2 R. J. Cummings, G. Barbet, G. Bongers, B. M. Hartmann, K. Gettler, L. Muniz, G. C. Furtado, J. Cho, S. A. Lira, J. M. Blander,
Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565–569 (2016).
3 S. Gordon, A. Plüddemann, Macrophage Clearance of Apoptotic Cells: A Critical Assessment. Front. Immunol. 9, 127 (2018).
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https://www.science.org/doi/10.1126/science.abo7027 3/6
7/4/24, 16:20 Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages | Science
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