The Tolerogenic Function of Annexins on Apoptotic Cells Is Mediated by the Annexin Core Domain

Linke, Björn; Abeler-Dörner, Lucie; Jahndel, Veronika; Kurz, Alexandra; Mahr, Andrea; Pfrang, Sandra; Linke, Linda; Krammer, Peter H.; Weyd, Heiko

doi:10.4049/jimmunol.1401299

Cited by 28 publications

(32 citation statements)

References 70 publications

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“…We found in the immunoresponsive TCGA subset of endometrial carcinomas (characterized by higher expression levels of immune response-related genes) that CD73 expression levels were significantly lower compared with those in the hormonal subset (characterized by higher expression levels of hormone receptors and genes induced by estrogen; Supplemental Figure 1C). Genes that characterize the immunoresponsive subset (CD74, CD14, TNFRSF1B, and CEBPD) have been shown to both activate and suppress immune responses (79)(80)(81)(82)(83)(84). No differences in inflammatory cell infiltrates were seen in the different endometrial carcinoma subtypes (Supplemental Figure 4 Figure 12) and colon (73,74) epithelial cells, innate and adaptive immune cells (75), and endothelial cells (23,76,77).…”

Section: Discussionmentioning

confidence: 99%

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

Bowser¹,

Blackburn²,

Shipley³

et al. 2015

Journal of Clinical Investigation

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Ecto-5'-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell-mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization-dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42-dependent conformational change of the actin-related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, β-catenin, and Na(+)K(+) ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described.

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Section: Discussionmentioning

confidence: 99%

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

Bowser¹,

Blackburn²,

Shipley³

et al. 2015

Journal of Clinical Investigation

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“…47 Annexins A5 and A13 also suppress dendritic cell activation for apoptotic cell-derived antigens, resulting in immunogenic tolerance. 48 However, deficiency in individual annexins did not show an obvious phenotype such as autoimmunity, suggesting that annexin proteins may have a redundant function. Thus, it remains to be defined whether annexin proteins are tolerogenic factors to suppress immune responses for apoptotic cell-derived antigens.…”

Section: Tolerogenic Signalsmentioning

confidence: 99%

Engulfment signals and the phagocytic machinery for apoptotic cell clearance

2017

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The clearance of apoptotic cells is an essential process for tissue homeostasis. To this end, cells undergoing apoptosis must display engulfment signals, such as ‘find-me' and ‘eat-me' signals. Engulfment signals are recognized by multiple types of phagocytic machinery in phagocytes, leading to prompt clearance of apoptotic cells. In addition, apoptotic cells and phagocytes release tolerogenic signals to reduce immune responses against apoptotic cell-derived self-antigens. Here we discuss recent advances in our knowledge of engulfment signals, the phagocytic machinery and the signal transduction pathways for apoptotic cell engulfment.

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“…During apoptosis, phosphatidylserine (PtdSer), calreticulin, the annexins A5 and A13, and DNA are some of the intracellular molecules that become exposed on the apoptotic cell surface as ACAMPs. PtdSer, and the annexins A5 and A13 externalized on the apoptotic cell membrane exert potent immune‐regulatory effects on target leukocytes . Apoptotic cells also suppress the immune response through the release of soluble mediators, including IL‐10, TGF‐β, and annexin A1 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease

Morelli

Larregina

2016

Stem Cells

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The main limitations to the success of transplantation are the anti-graft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the anti-donor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system.

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The Tolerogenic Function of Annexins on Apoptotic Cells Is Mediated by the Annexin Core Domain

Cited by 28 publications

References 70 publications

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

Engulfment signals and the phagocytic machinery for apoptotic cell clearance

Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease

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