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Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages

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Abstract

Apoptotic cells express eat-me signals which are recognized by several receptors mainly on professional phagocytes of the mononuclear phagocyte system. This “engulfment synapse” can define a safe and effective clearance of apoptotic cells in order to maintain tissue homeostasis in the entire body. We show that the expression of four genes related to apoptotic cell clearance is strongly up-regulated in human macrophages 30 min after administration of apoptotic neutrophils. Out of these the significant role of the up-regulated intercellular adhesion molecule 3 (ICAM3) in phagocytosis of apoptotic neutrophils could be demonstrated in macrophages by gene silencing as well as treatment with blocking antibodies. Blocking ICAM3 on the surface of apoptotic neutrophils also resulted in their decreased uptake which confirmed its role as an eat-me signal expressed by apoptotic cells. In macrophages but not in neutrophils silencing and blocking integrin alphaL and beta2 components of lymphocyte function-associated antigen 1 (LFA-1), which can strongly bind ICAM3, resulted in a decreased phagocytosis of apoptotic cells indicating its possible role to recognize ICAM3 on the surface of apoptotic neutrophils. Finally, we report that engulfing portals formed in macrophages during phagocytosis are characterized by accumulation of ICAM3, integrin alphaL and beta2 which show co-localization on the surface of phagocytes. Furthermore, their simultaneous knock-down in macrophages resulted in a marked deficiency in phagocytosis and a slight decrease in the anti-inflammatory effect of apoptotic neutrophils. We propose that ICAM3 and LFA-1 act as recognition receptors in the phagocytosis portals of macrophages for engulfment of apoptotic neutrophils.

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Abbreviations

ADORA2A:

Adenosine A2A receptor

APC:

Antigen presenting cell

Ct:

Comparative threshold

DC-SIGN:

Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

FC:

Fold change

FPRL1:

Formyl peptide receptor-like 1

HMDM:

Human monocyte derived macrophage

ICAM3:

Intercellular adhesion molecule 3

ITC:

Isotype control

ITGAL:

Integrin alphaL

ITGB2:

Integrin beta2

KD:

Knock-down

LFA-1:

Lymphocyte function-associated antigen 1

LPS:

Lipopolysaccharides

M-CSF:

Macrophage colony-stimulating factor

PCD:

Programmed cell death

Scr:

Scrambled

siRNA:

Small interfering ribonucleic acid

THBS1:

Thrombospondin 1

TLDA:

TaqMan low-density array

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Acknowledgments

This work has been supported by Grants from the Hungarian Scientific Research Fund (OTKA NK 105046, K 61868), TÁMOP 4.2.1./B-09/1/KONV-2010-0007 and TÁMOP-4.2.2/B-10/1-2010-0024 projects implemented through the New Hungary Development Plan, co-financed by the European Social Fund, EU FP7 TRANSCOM IAPP 251506, TRANSPATH ITN 289964 and NKTH NTP Schizo08. We thank Dr. Zsuzsa Szondy for her consultation and for reviewing the manuscript. We acknowledge Jennifer Nagy and Szilvia Szalóki for excellent technical assistance.

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Correspondence to László Fésüs.

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E. Kristóf and G. Zahuczky contributed equally to this study.

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Kristóf, E., Zahuczky, G., Katona, K. et al. Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages. Apoptosis 18, 1235–1251 (2013). https://doi.org/10.1007/s10495-013-0873-z

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