Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

Martin, Myriam; Leffler, Jonatan; Blom, Anna M.

doi:10.1074/jbc.m112.341339

Cited by 103 publications

(66 citation statements)

References 52 publications

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“…TSP-1 and milk-fat globulin-E8 (MFG-E8) also bind to PS and are recognized by the integrin αv/β3/CD36 or integrin αv/β3/TG2 receptor complexes, respectively (36–38). The collectin family member serum protein C1q also serves as a bridging molecule by recognizing annexin A2 and A5 on the apoptotic cells (39) and binding either SCARF1 scavenger receptor or the calreticulin associated LRP1/CD91 receptor on phagocytes (39, 40). The LPS coreceptor CD14 can also act as a tethering receptor for apoptotic cells, albeit its exact ligand remains unknown (41).…”

Section: Mechanisms Contributing To Efficient Phagocytosis Of Apoptotmentioning

confidence: 99%

Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

et al. 2014

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In healthy individuals, billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis) must be efficient to prevent secondary necrosis and the consequent release of pro-inflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of either genetic anomalies and/or a persistent disease state, contributes to the establishment and progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases, obesity, type 2 diabetes, or atherosclerosis. During the past decade, our knowledge about the mechanism of efferocytosis has significantly increased, providing therapeutic targets through which impaired phagocytosis of apoptotic cells and the consequent inflammation could be influenced in these diseases.

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Section: Mechanisms Contributing To Efficient Phagocytosis Of Apoptotmentioning

confidence: 99%

Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

et al. 2014

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“…The binding of C1q to the apoptotic cell surface is a multimolecular event which has not yet been completely deciphered. We and others have characterized a number of the molecules that mark the apoptotic cell and serve as C1q ligands via interaction with its globular regions (C1qGR), such as phosphatidylserine (PS) [15], DNA [16,17], annexins [18], GAPDH [19] and calreticulin (CRT) [20]. To add complexity, some of these molecules have been shown to interact, e.g.…”

Section: Introductionmentioning

confidence: 99%

Relative Contribution of C1q and Apoptotic Cell-Surface Calreticulin to Macrophage Phagocytosis

Verneret¹,

Tacnet-Delorme²,

Osman³

et al. 2014

J Innate Immun

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C1q has been shown to recognize apoptotic cells, to enhance their uptake and to modulate cytokine release by phagocytes and thus promote immune tolerance. Surface-exposed calreticulin (CRT), known as a C1q receptor, is also considered to be an early eat-me signal that enhances the phagocytosis of apoptotic cells and is capable of eliciting an immunogenic response. However, the molecular mechanisms that trigger these functions are not clear. We hypothesized that CRT and C1q might act together in these processes. We first showed, by means of fluorescence resonance energy transfer (FRET), that CRT interacts with the C1q globular region at the surface of early apoptotic cells. Next, we pointed out that knockdown of CRT on early apoptotic HeLa cells impairs the enhancement effect of C1q on their uptake by THP-1 monocyte-derived macrophages. Furthermore, a deficiency of CRT induces contrasting effects on cytokine release by THP-1 macrophages, increasing interleukin (IL)-6 and monocyte chemotactic protein 1/CCL2 and decreasing IL-8. Remarkably, these effects were greatly reduced when apoptotic cells were opsonized by C1q, which counterbalanced the effect of the CRT deficiency. These results demonstrate that CRT-C1q interaction is involved in the C1q bridging function and they highlight the particular ability of C1q to control the phagocyte inflammatory status, i.e. by integrating the molecular changes that could occur at the surface of dying cells.

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“…Because C1q binding to AC was low in NHS (Fig. 1C, top row), as also shown by others [15,41–43], we supplemented 10% NHS with 15 μg/ml of puriμed human C1q to increase detection (Fig. 1C, bottom row), and then asked whether TNT003 affected C1q binding to late AC in the presence of other serum factors.…”

Section: Resultsmentioning

confidence: 95%

Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

Colonna

Parry²,

Panicker³

et al. 2016

Clinical Immunology

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Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.

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Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

Cited by 103 publications

References 52 publications

Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

Impaired Clearance of Apoptotic Cells in Chronic Inflammatory Diseases: Therapeutic Implications

Relative Contribution of C1q and Apoptotic Cell-Surface Calreticulin to Macrophage Phagocytosis

Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

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