Macrophages engulfing apoptotic cells produce nonclassical retinoids to enhance their phagocytic capacity

Zsolt Sarang Gergely Joós, Éva Garabuczi, Ralph Rühl, Christopher D. Gregory, Z. Szondy

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Previous work in our laboratory has shown that transglutaminase 2 (TG2) acting as a coreceptor for integrin β3 is required for proper phagocytosis of apoptotic cells. In the absence of TG2, systemic lupus erythematosus-like autoimmunity develops in mice, similarly to other mice characterized by a deficiency in the clearance of apoptotic cells. In this study, we demonstrate that increasing TG2 expression alone in wild-type macrophages is not sufficient to enhance engulfment. However, during engulfment, the lipid content of the apoptotic cells triggers the lipid-sensing receptor liver X receptor (LXR), which in response upregulates the expression of the phagocytic receptor Mer tyrosine kinase and the phagocytosis-related ABCA1, and that of retinaldehyde dehydrogenases leading to the synthesis of a nonclassical retinoid. Based on our retinoid analysis, this compound might be a dihydro-retinoic acid derivative. The novel retinoid then contributes to the upregulation of further phagocytic receptors including TG2 by ligating retinoic acid receptors. Inhibition of retinoid synthesis prevents the enhanced phagocytic uptake induced by LXR ligation. Our data indicate that stimulation of LXR enhances the engulfment of apoptotic cells via regulating directly and indirectly the expression of a range of phagocytosis-related molecules, and its signaling pathway involves the synthesis of a nonclassical retinoid. We propose that retinoids could be used for enhancing the phagocytic capacity of macrophages in diseases such as systemic lupus erythematosus, where impaired phagocytosis of apoptotic cells plays a role in the pathogenesis of the disease.

Original languageEnglish
Pages (from-to)5730-5738
Number of pages9
JournalJournal of Immunology
Volume192
Issue number12
DOIs
Publication statusPublished - Jun 15 2014

Fingerprint

Retinoids
Macrophages
Cytophagocytosis
Phagocytosis
Systemic Lupus Erythematosus
Up-Regulation
Retinaldehyde
Lipids
Retinoic Acid Receptors
Receptor Protein-Tyrosine Kinases
Tretinoin
Autoimmunity
Integrins
Ligation
Oxidoreductases
transglutaminase 2
Liver X Receptors

ASJC Scopus subject areas

  • Immunology

Cite this

Macrophages engulfing apoptotic cells produce nonclassical retinoids to enhance their phagocytic capacity. / Joós, Zsolt Sarang Gergely; Garabuczi, Éva; Rühl, Ralph; Gregory, Christopher D.; Szondy, Z.

In: Journal of Immunology, Vol. 192, No. 12, 15.06.2014, p. 5730-5738.

Research output: Contribution to journalArticle

Joós, Zsolt Sarang Gergely ; Garabuczi, Éva ; Rühl, Ralph ; Gregory, Christopher D. ; Szondy, Z. / Macrophages engulfing apoptotic cells produce nonclassical retinoids to enhance their phagocytic capacity. In: Journal of Immunology. 2014 ; Vol. 192, No. 12. pp. 5730-5738.
@article{79ef8835dc6743a2a055af0fa1c2c53f,
title = "Macrophages engulfing apoptotic cells produce nonclassical retinoids to enhance their phagocytic capacity",
abstract = "Previous work in our laboratory has shown that transglutaminase 2 (TG2) acting as a coreceptor for integrin β3 is required for proper phagocytosis of apoptotic cells. In the absence of TG2, systemic lupus erythematosus-like autoimmunity develops in mice, similarly to other mice characterized by a deficiency in the clearance of apoptotic cells. In this study, we demonstrate that increasing TG2 expression alone in wild-type macrophages is not sufficient to enhance engulfment. However, during engulfment, the lipid content of the apoptotic cells triggers the lipid-sensing receptor liver X receptor (LXR), which in response upregulates the expression of the phagocytic receptor Mer tyrosine kinase and the phagocytosis-related ABCA1, and that of retinaldehyde dehydrogenases leading to the synthesis of a nonclassical retinoid. Based on our retinoid analysis, this compound might be a dihydro-retinoic acid derivative. The novel retinoid then contributes to the upregulation of further phagocytic receptors including TG2 by ligating retinoic acid receptors. Inhibition of retinoid synthesis prevents the enhanced phagocytic uptake induced by LXR ligation. Our data indicate that stimulation of LXR enhances the engulfment of apoptotic cells via regulating directly and indirectly the expression of a range of phagocytosis-related molecules, and its signaling pathway involves the synthesis of a nonclassical retinoid. We propose that retinoids could be used for enhancing the phagocytic capacity of macrophages in diseases such as systemic lupus erythematosus, where impaired phagocytosis of apoptotic cells plays a role in the pathogenesis of the disease.",
author = "Jo{\'o}s, {Zsolt Sarang Gergely} and {\'E}va Garabuczi and Ralph R{\"u}hl and Gregory, {Christopher D.} and Z. Szondy",
year = "2014",
month = "6",
day = "15",
doi = "10.4049/jimmunol.1400284",
language = "English",
volume = "192",
pages = "5730--5738",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "12",

}

TY - JOUR

T1 - Macrophages engulfing apoptotic cells produce nonclassical retinoids to enhance their phagocytic capacity

AU - Joós, Zsolt Sarang Gergely

AU - Garabuczi, Éva

AU - Rühl, Ralph

AU - Gregory, Christopher D.

AU - Szondy, Z.

PY - 2014/6/15

Y1 - 2014/6/15

N2 - Previous work in our laboratory has shown that transglutaminase 2 (TG2) acting as a coreceptor for integrin β3 is required for proper phagocytosis of apoptotic cells. In the absence of TG2, systemic lupus erythematosus-like autoimmunity develops in mice, similarly to other mice characterized by a deficiency in the clearance of apoptotic cells. In this study, we demonstrate that increasing TG2 expression alone in wild-type macrophages is not sufficient to enhance engulfment. However, during engulfment, the lipid content of the apoptotic cells triggers the lipid-sensing receptor liver X receptor (LXR), which in response upregulates the expression of the phagocytic receptor Mer tyrosine kinase and the phagocytosis-related ABCA1, and that of retinaldehyde dehydrogenases leading to the synthesis of a nonclassical retinoid. Based on our retinoid analysis, this compound might be a dihydro-retinoic acid derivative. The novel retinoid then contributes to the upregulation of further phagocytic receptors including TG2 by ligating retinoic acid receptors. Inhibition of retinoid synthesis prevents the enhanced phagocytic uptake induced by LXR ligation. Our data indicate that stimulation of LXR enhances the engulfment of apoptotic cells via regulating directly and indirectly the expression of a range of phagocytosis-related molecules, and its signaling pathway involves the synthesis of a nonclassical retinoid. We propose that retinoids could be used for enhancing the phagocytic capacity of macrophages in diseases such as systemic lupus erythematosus, where impaired phagocytosis of apoptotic cells plays a role in the pathogenesis of the disease.

AB - Previous work in our laboratory has shown that transglutaminase 2 (TG2) acting as a coreceptor for integrin β3 is required for proper phagocytosis of apoptotic cells. In the absence of TG2, systemic lupus erythematosus-like autoimmunity develops in mice, similarly to other mice characterized by a deficiency in the clearance of apoptotic cells. In this study, we demonstrate that increasing TG2 expression alone in wild-type macrophages is not sufficient to enhance engulfment. However, during engulfment, the lipid content of the apoptotic cells triggers the lipid-sensing receptor liver X receptor (LXR), which in response upregulates the expression of the phagocytic receptor Mer tyrosine kinase and the phagocytosis-related ABCA1, and that of retinaldehyde dehydrogenases leading to the synthesis of a nonclassical retinoid. Based on our retinoid analysis, this compound might be a dihydro-retinoic acid derivative. The novel retinoid then contributes to the upregulation of further phagocytic receptors including TG2 by ligating retinoic acid receptors. Inhibition of retinoid synthesis prevents the enhanced phagocytic uptake induced by LXR ligation. Our data indicate that stimulation of LXR enhances the engulfment of apoptotic cells via regulating directly and indirectly the expression of a range of phagocytosis-related molecules, and its signaling pathway involves the synthesis of a nonclassical retinoid. We propose that retinoids could be used for enhancing the phagocytic capacity of macrophages in diseases such as systemic lupus erythematosus, where impaired phagocytosis of apoptotic cells plays a role in the pathogenesis of the disease.

UR - http://www.scopus.com/inward/record.url?scp=84902195829&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902195829&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1400284

DO - 10.4049/jimmunol.1400284

M3 - Article

C2 - 24850721

AN - SCOPUS:84902195829

VL - 192

SP - 5730

EP - 5738

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 12

ER -