Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

Gaipl, Udo S.; Beyer, Thomas; Heyder, Petra; Kuenkele, Susanne; Böttcher, Andrea; Voll, Reinhard; Kalden, Joachim R.; Herrmann, Martin

doi:10.1002/art.20034

Cited by 105 publications

(91 citation statements)

References 57 publications

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“…BÖ TTCHER ET AL chromatin and is necessary for effective uptake of necrotic cell-derived chromatin by activated monocytes (34). Regarding the uptake of necrotic cells by professional phagocytes such as macrophages, we found that C1q markedly contributed to the clearance of whole necrotic cells.…”

mentioning

confidence: 65%

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Böttcher

Gaipl

Fürnrohr³

et al. 2006

Arthritis & Rheumatism

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Objective. Uningested dead cells may be an important source of autoantigens and may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). Multiple receptors involved in the clearance of apoptotic cells have been described; however, little is known about the receptors and ligands involved in uptake of necrotic cells that release autoantigens as well.Methods. The uptake of autologous necrotic peripheral blood lymphocytes into human monocyte-derived macrophages was qualitatively and quantitatively monitored by confocal microscopy and 2-color flow cytometry, respectively. Blocking experiments were performed to examine the receptors and molecules involved in the phagocytosis of necrotic cells. Cytokine secretion by lipopolysaccharide-activated monocytes and macrophages was determined by enzyme-linked immunosorbent assay.

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confidence: 65%

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Böttcher

Gaipl

Fürnrohr³

et al. 2006

Arthritis & Rheumatism

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“…There is increasing interest in necrotic cells, particularly when they arise as the result of defective clearance of apoptotic cells, as reservoirs of altered autoantigens and danger signals that could contribute to the generation of autoantibody responses in rheumatic diseases (36)(37)(38)(39). A current hypothesis is that impaired phagocytic removal of apoptotic cells may cause accumulation of secondary necrotic cells in germinal centers of secondary lymphoid organs, leading to exposure by the immune system to high concentrations of altered forms of autoantigens for which tolerance has not been previously achieved (36,37).…”

Section: Discussionmentioning

confidence: 99%

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Pacheco¹,

Servin²,

Dang³

et al. 2005

Arthritis & Rheumatism

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Objective. Autoantibodies to DNA topoisomerase I (topo I) are associated with diffuse systemic sclerosis (SSc), appear to be antigen driven, and may be triggered by cryptic epitopes exposed during in vivo topo I fragmentation. These autoantibodies recognize topo I and fragments of this autoantigen generated during apoptosis and necrosis. We undertook this study to determine whether lysosomal cathepsins are involved in topo I fragmentation during necrosis.Methods. Topo I cleavage during necrosis was assessed by immunoblotting of lysates from L929 fibroblasts exposed to tumor necrosis factor ␣ (

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“…43 Dex was purchased from Merck Biosciences (Darmstadt, Germany). ActD and CHX were from Sigma and Carl Roth (Karlsruhe, Germany), respectively.…”

Section: Irradiation-induced Thymus Atrophy C57bl/6 Mice and Mfg-e8mentioning

confidence: 99%

Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

et al. 2013

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The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8 À / À mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs in vitro and in vivo. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.

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Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin

Cited by 105 publications

References 57 publications

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

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