Retinoids produced by macrophages engulfing apoptotic cells contribute to the appearance of transglutaminase 2 in apoptotic thymocytes

Garabuczi, Éva; Kiss, Beáta; Felszeghy, Szabolcs; Tsay, Gregory J.; Fésüs, László; Szondy, Zsuzsa

doi:10.1007/s00726-011-1119-4

Cited by 28 publications

(25 citation statements)

References 20 publications

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“…As we have reported previously, we found that agonists of all these three receptors promoted the mRNA expression of RALDH1 in macrophages (data published in Ref. 36).…”

Section: Ligation Of Lxrs Induces Retinoid Production In Peritoneal Msupporting

confidence: 67%

“…Because it is difficult to isolate sufficient macrophages to detect their retinoid production, we decided to analyze whole thymus tissue. In the thymus, we have shown previously the increased RALDH expression of macrophages and that of LacZ in the thymus of RARE LacZ mice after in vivo apoptosis induction (36). LacZ expression in RARE LacZ mice indicates the production of endogenously formed RAR-activating ligands, and because its dexamethasone-induced induction was prevented by DEAB, our data suggested that these bioactive compounds were produced via an RALDH-dependent step in vivo.…”

Section: Macrophages Engulfing Apoptotic Cells Do Not Produce the Clamentioning

confidence: 70%

“…Previous studies in our laboratory have shown that the in vivo apoptosis induction of thymocytes is coupled to an enhanced retinoid production in the thymus, and the cells that expressed retinaldehyde dehydrogenases (RALDHs) responsible for retinoic acid production were the engulfing macrophages (36). Apoptotic cell uptake in vitro also triggered the expression of RALDHs in macrophages, indicating that the uptake of apoptotic cells is coupled to retinoid synthesis.…”

Section: Ligation Of Lxrs Induces Retinoid Production In Peritoneal Mmentioning

confidence: 91%

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Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

Sarang

Joós

Garabuczi

et al. 2014

The Journal of Immunology

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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.

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“…As we have reported previously, we found that agonists of all these three receptors promoted the mRNA expression of RALDH1 in macrophages (data published in Ref. 36).…”

Section: Ligation Of Lxrs Induces Retinoid Production In Peritoneal Msupporting

confidence: 67%

Section: Macrophages Engulfing Apoptotic Cells Do Not Produce the Clamentioning

confidence: 70%

Section: Ligation Of Lxrs Induces Retinoid Production In Peritoneal Mmentioning

confidence: 91%

See 1 more Smart Citation

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

Sarang

Joós

Garabuczi

et al. 2014

The Journal of Immunology

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“…Our observation that a subset of mesenchymal cells maintains the ability to generate RA after birth suggests that RA signals may help to regulate TEC homeostasis in the adult. Consistent with this possibility, endogenous RA signaling in the postnatal thymus has been demonstrated using RA-reporter mice (36,67). Based on the presence of Aldh1a1 expression in TECs and the detection of dexamethasone-induced Aldh1a1 and Aldh1a2 in thymic macrophages (36,67), these studies proposed that TECs and macrophages contribute to the generation of RA in the steady-state and glucocorticoid-stimulated thymus, respectively.…”

Section: Discussionmentioning

confidence: 76%

“…Consistent with this possibility, endogenous RA signaling in the postnatal thymus has been demonstrated using RA-reporter mice (36,67). Based on the presence of Aldh1a1 expression in TECs and the detection of dexamethasone-induced Aldh1a1 and Aldh1a2 in thymic macrophages (36,67), these studies proposed that TECs and macrophages contribute to the generation of RA in the steady-state and glucocorticoid-stimulated thymus, respectively. By flow cytometry, we identified two major mesenchymal cell populations in the adult thymus based on expression of Ly51 and gp38: Ly51 int gp38 + and Ly51 hi gp38 2 cells.…”

Section: Discussionmentioning

confidence: 76%

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

Sitnik

Kotarsky

White

et al. 2012

The Journal of Immunology

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The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance of the epithelial compartment of the thymus in T cell development and selection, the potential role of RA in the regulation of thymic cortical and medullary epithelial cell homeostasis has yet to be addressed. In this study, using fetal thymus organ cultures, we demonstrate that endogenous RA signaling promotes thymic epithelial cell (TEC) cell-cycle exit and restricts TEC cellularity preferentially in the cortical TEC compartment. Combined gene expression, biochemical, and functional analyses identified mesenchymal cells as the major source of RA in the embryonic thymus. In reaggregate culture experiments, thymic mesenchyme was required for RA-dependent regulation of TEC expansion, highlighting the importance of mesenchyme-derived RA in modulating TEC turnover. The RA-generating potential of mesenchymal cells was selectively maintained within a discrete Ly51intgp38+ subset of Ly51+ mesenchyme in the adult thymus, suggesting a continual role for mesenchymal cell-derived RA in postnatal TEC homeostasis. These findings identify RA signaling as a novel mechanism by which thymic mesenchyme influences TEC development.

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Thymocyte death by neglect: Contribution of engulfing macrophages

Szondy

Garabuczi²,

Tóth³

et al. 2012

Eur J Immunol

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The thymus provides the microenvironment in which thymocytes develop into mature T cells, and interactions with thymic stromal cells are thought to provide the necessary signals for thymocyte maturation. Recognition of self-MHC by T cells is a basic requirement for mature T-cell functions, and those thymocytes that do not recognize the peptide-loaded self-MHC molecules found in the thymus, and therefore lack a TCR signal, undergo a default death pathway named "death by neglect" in the thymic cortex. In the absence of this TCR signaling, it has been suggested that binding of glucocorticoids toor the ligation of certain cell surface molecules, such as CD8, CD24, CD45, or CD99 on -these neglected thymocytes will induce them to enter the apoptotic program. Apoptotic thymocytes are cleared by the surrounding macrophages and, as a consequence, these macrophages are known to release various molecules, such as adenosine, retinoids, TGF-β, ATP, and carbon monoxide. Interestingly, all these molecules have been described to induce or promote apoptosis in thymocytes in the absence of TCR signaling. Here, we propose that thymic macrophages, because they continually engulf apoptotic cells, might constantly provide these cell death-inducing signals, and thus contribute to the formation of a thymic milieu that ensures the effective induction of "death by neglect".

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Retinoids produced by macrophages engulfing apoptotic cells contribute to the appearance of transglutaminase 2 in apoptotic thymocytes

Cited by 28 publications

References 20 publications

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

Thymocyte death by neglect: Contribution of engulfing macrophages

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