DEL-1 promotes macrophage efferocytosis and clearance of inflammation

Ioannis Kourtzelis; Xiaofei Li; Ioannis Mitroulis; Daniel Grosser; Tetsuhiro Kajikawa; Baomei Wang; Michal Grzybek; Janusz von Renesse; Aleksander Czogalla; Maria Troullinaki; Anaisa Ferreira; Christian Doreth; Klara Ruppova; Lan-Sun Chen; Kavita Hosur; Jong-Hyung Lim; Kyoung-Jin Chung; Sylvia Grossklaus; Anne Kathrin Tausche; Leo A B Joosten; Niki M Moutsopoulos; Ben Wielockx; Antonio Castrillo; Jonathan M Korostoff; Ünal Coskun; George Hajishengallis; Triantafyllos Chavakis

doi:10.1038/s41590-018-0249-1

DEL-1 promotes macrophage efferocytosis and clearance of inflammation

Ioannis Kourtzelis, Xiaofei Li, Ioannis Mitroulis, Daniel Grosser, Tetsuhiro Kajikawa, Baomei Wang, Michal Grzybek, Janusz von Renesse, Aleksander Czogalla, Maria Troullinaki, Anaisa Ferreira, Christian Doreth, Klara Ruppova, Lan-Sun Chen, Kavita Hosur, Jong-Hyung Lim, Kyoung-Jin Chung, Sylvia Grossklaus, Anne Kathrin Tausche, Leo A B JoostenNiki M Moutsopoulos, Ben Wielockx, Antonio Castrillo, Jonathan M Korostoff, Ünal Coskun, George Hajishengallis, Triantafyllos Chavakis

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.

Original language	English
Pages (from-to)	40-49
Number of pages	10
Journal	Nature immunology
Volume	20
Issue number	1
Early online date	19 Nov 2018
DOIs	https://doi.org/10.1038/s41590-018-0249-1
Publication status	Published - Jan 2019

Keywords

Adult
Animals
Carrier Proteins/genetics
Cellular Reprogramming
Cytokines/metabolism
Gene Expression Regulation
Humans
Inflammation/chemically induced
Intercellular Signaling Peptides and Proteins
K562 Cells
Liver X Receptors/metabolism
Macrophages/physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils/immunology
Periodontitis/immunology
Phagocytosis

Access to Document

10.1038/s41590-018-0249-1

Cite this

Kourtzelis, I., Li, X., Mitroulis, I., Grosser, D., Kajikawa, T., Wang, B., Grzybek, M., von Renesse, J., Czogalla, A., Troullinaki, M., Ferreira, A., Doreth, C., Ruppova, K., Chen, L.-S., Hosur, K., Lim, J.-H., Chung, K.-J., Grossklaus, S., Tausche, A. K., ... Chavakis, T. (2019). DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nature immunology, 20(1), 40-49. https://doi.org/10.1038/s41590-018-0249-1

@article{f170ae6d108d40eda00d95a02756a549,

title = "DEL-1 promotes macrophage efferocytosis and clearance of inflammation",

abstract = "Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.",

keywords = "Adult, Animals, Carrier Proteins/genetics, Cellular Reprogramming, Cytokines/metabolism, Gene Expression Regulation, Humans, Inflammation/chemically induced, Intercellular Signaling Peptides and Proteins, K562 Cells, Liver X Receptors/metabolism, Macrophages/physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils/immunology, Periodontitis/immunology, Phagocytosis",

author = "Ioannis Kourtzelis and Xiaofei Li and Ioannis Mitroulis and Daniel Grosser and Tetsuhiro Kajikawa and Baomei Wang and Michal Grzybek and {von Renesse}, Janusz and Aleksander Czogalla and Maria Troullinaki and Anaisa Ferreira and Christian Doreth and Klara Ruppova and Lan-Sun Chen and Kavita Hosur and Jong-Hyung Lim and Kyoung-Jin Chung and Sylvia Grossklaus and Tausche, {Anne Kathrin} and Joosten, {Leo A B} and Moutsopoulos, {Niki M} and Ben Wielockx and Antonio Castrillo and Korostoff, {Jonathan M} and {\"U}nal Coskun and George Hajishengallis and Triantafyllos Chavakis",

year = "2019",

month = jan,

doi = "10.1038/s41590-018-0249-1",

language = "English",

volume = "20",

pages = "40--49",

journal = "Nature immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "1",

}

Kourtzelis, I, Li, X, Mitroulis, I, Grosser, D, Kajikawa, T, Wang, B, Grzybek, M, von Renesse, J, Czogalla, A, Troullinaki, M, Ferreira, A, Doreth, C, Ruppova, K, Chen, L-S, Hosur, K, Lim, J-H, Chung, K-J, Grossklaus, S, Tausche, AK, Joosten, LAB, Moutsopoulos, NM, Wielockx, B, Castrillo, A, Korostoff, JM, Coskun, Ü, Hajishengallis, G & Chavakis, T 2019, 'DEL-1 promotes macrophage efferocytosis and clearance of inflammation', Nature immunology, vol. 20, no. 1, pp. 40-49. https://doi.org/10.1038/s41590-018-0249-1

TY - JOUR

T1 - DEL-1 promotes macrophage efferocytosis and clearance of inflammation

AU - Kourtzelis, Ioannis

AU - Li, Xiaofei

AU - Mitroulis, Ioannis

AU - Grosser, Daniel

AU - Kajikawa, Tetsuhiro

AU - Wang, Baomei

AU - Grzybek, Michal

AU - von Renesse, Janusz

AU - Czogalla, Aleksander

AU - Troullinaki, Maria

AU - Ferreira, Anaisa

AU - Doreth, Christian

AU - Ruppova, Klara

AU - Chen, Lan-Sun

AU - Hosur, Kavita

AU - Lim, Jong-Hyung

AU - Chung, Kyoung-Jin

AU - Grossklaus, Sylvia

AU - Tausche, Anne Kathrin

AU - Joosten, Leo A B

AU - Moutsopoulos, Niki M

AU - Wielockx, Ben

AU - Castrillo, Antonio

AU - Korostoff, Jonathan M

AU - Coskun, Ünal

AU - Hajishengallis, George

AU - Chavakis, Triantafyllos

PY - 2019/1

Y1 - 2019/1

N2 - Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.

AB - Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.

KW - Adult

KW - Animals

KW - Carrier Proteins/genetics

KW - Cellular Reprogramming

KW - Cytokines/metabolism

KW - Gene Expression Regulation

KW - Humans

KW - Inflammation/chemically induced

KW - Intercellular Signaling Peptides and Proteins

KW - K562 Cells

KW - Liver X Receptors/metabolism

KW - Macrophages/physiology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neutrophils/immunology

KW - Periodontitis/immunology

KW - Phagocytosis

UR - http://www.scopus.com/inward/record.url?scp=85056869028&partnerID=8YFLogxK

U2 - 10.1038/s41590-018-0249-1

DO - 10.1038/s41590-018-0249-1

M3 - Article

C2 - 30455459

SN - 1529-2908

VL - 20

SP - 40

EP - 49

JO - Nature immunology

JF - Nature immunology

IS - 1

ER -

DEL-1 promotes macrophage efferocytosis and clearance of inflammation

Abstract

Keywords

Access to Document

Other files and links

Profiles

Ioannis Kourtzelis

Cite this