C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and Cd91 Initiates Macropinocytosis and Uptake of Apoptotic Cells

Ogden, Carol Anne; deCathelineau, Aimee M.; Hoffmann, Peter; Bratton, Donna L.; Ghebrehiwet, Berhane; Fadok, Valerie A.; Henson, Peter M.

doi:10.1084/jem.194.6.781

Cited by 1,037 publications

(979 citation statements)

References 124 publications

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“…However, this leaves us with the obvious question, what kind of effector machinery does MBL utilize to remove apoptotic cells? Two recent studies have brought further insight to this question indicating that both C1q, SP-A, SP-D as well as MBL utilize the calreticulin/CD91 complex on phagocytes as acceptor site for sequestration of apoptotic material [9,16]. Consistent with these studies, we demonstrated that opsonization of apoptotic cells with MBL facilitated their uptake by macrophages.…”

Section: Discussionsupporting

confidence: 89%

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Mannose‐binding lectin engagement with late apoptotic and necrotic cells

et al. 2003

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The serum opsonin mannose-binding lectin (MBL) has been shown to be involved in the handling of apoptotic cells. However, at what stage in the process this happens and whether this mediates activation of complement is unknown. Cells rendered apoptotic or necrotic were incubated with purified MBL/MBL-associated serine protease (MASP) complexes and assessed by flow cytometry and fluorescence microscopy. MBL bound specifically to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells. Binding of MBL could be inhibited by EDTA as well as with an antibody against the CRD region. Addition of C1q, another serum opsonin involved in the handling of apoptotic cells, prior to MBL partly inhibited MBL binding to apoptotic cells and vice versa. MBL/ MASP could initiate deposition of purified complement C4 on the target cells. However, addition of MBL/MASP to whole serum deficient for both C1q and MBL did not enhance deposition of C4, but MBL enhanced phagocytosis of apoptotic cells by macrophages. These results demonstrate that MBL interacts with structures exposed on cells rendered late apoptotic or necrotic and facilitates uptake by macrophages. Thus, MBL may promote noninflammatory sequestration of dying host cells.

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Section: Discussionsupporting

confidence: 89%

“…Moreover, the presence of MBL variant alleles is associated with increased risk of SLE (for a comprehensive analysis see [8]). Recent findings show that MBL binds to apoptotic cells and that both C1q and MBL use calreticulin and CD91 to initiate macropinocytosis and uptake of apoptotic cells by phagocytes [9].…”

Section: Introductionmentioning

confidence: 99%

Mannose‐binding lectin engagement with late apoptotic and necrotic cells

et al. 2003

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“…It is likely that such 26 TROELSEN ET AL endothelial cell damage would lead to the endothelial dysfunction that has been described in RA (39,40), which again is predictive of the development of coronary artery disease (41). It is of particular interest that MBL, among other factors, binds N-acetylglucosamine and damaged host cells, exposing nucleic acids (42)(43)(44). Oxidative stress seems to expose structures on endothelial cells that promote binding of MBL (14).…”

Section: Discussionmentioning

confidence: 99%

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Troelsen¹,

Garred²,

Madsen³

et al. 2006

Arthritis Rheum

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Objective. Patients with rheumatoid arthritis (RA) have excess morbidity and mortality due to ischemic heart disease. It has been suggested that high serum levels of mannose-binding lectin (MBL) and agalactosyl IgG (IgG-G0) are associated with increased inflammation in RA. MBL also enhances inflammationmediated tissue injury during postischemic reperfusion. This study was undertaken to examine whether these factors are associated with increased risk of ischemic heart disease in RA.Methods. MBL alleles were genotyped in 229 Danish patients with RA. In addition, serum levels of MBL and IgG-G0 were measured. Incidences of ischemic heart disease, myocardial infarction, and death due to ischemic heart disease after the diagnosis of RA were assessed in a prospective study.Results. During a median followup of 9.5 years, ischemic heart disease was diagnosed in 8 of 27 patients with genetically determined high serum levels of MBL, as compared with 24 of the remaining 192 patients (data not available on 10 patients). After correction for other known risk factors, the hazard ratio (HR) was 3.6 (95% confidence interval [95% CI] 1.4-9.2). The corrected HR for myocardial infarction was 9.0 (95% CI 2.2-36.4).High serum levels of MBL also conferred an increased risk of death due to ischemic heart disease (age-and sex-adjusted HR 10.5, 95% CI 2.7-41.3). However, further analyses showed that these associations were present only in patients with high serum levels of IgG-G0.Conclusion. Genetically determined high serum levels of MBL and high serum levels of IgG-G0 are associated with increased risk of ischemic heart disease, myocardial infarction, and premature death in patients with RA.

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“…Defects in the recognition and uptake of apoptotic cells have been thought to contribute to the pathogenesis of autoimmunity in SLE (8,25). A disturbed clearance of apoptotic cells, as has been observed in some patients with SLE, facilitates the release of heat-shock proteins (33), nucleosomes (34), calreticulin (35,36), and other intracellular contents. In addition, modifications of these autoantigens during programmed cell death can render them more immunogenic (34,37,38).…”

Section: Discussionmentioning

confidence: 99%

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

Gaipl¹,

Beyer²,

Heyder³

et al. 2004

Arthritis & Rheumatism

105

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Objective. The efficient uptake of dying cells by phagocytes is essential to the avoidance of chronic inflammation. Some human autoimmune responses are thought to be driven by autoantigens from apoptotic or necrotic cells. We analyzed the role of C1q and DNase I in the disposal of necrotic cell-derived chromatin because deficiencies in these serum factors predispose to the development of systemic autoimmune disorders, such as systemic lupus erythematosus.Methods. Human necrotic peripheral blood lymphocytes were incubated in cell culture medium supplemented with various sera or serum components. Chromatin degradation was monitored by measuring the residual DNA content by flow cytometry. The uptake of necrotic cell-derived nuclei was analyzed by in vitro phagocytosis assays.Results. Reconstitution of C1q-depleted serum with C1q strongly increased its ability to degrade necrotic cell-derived chromatin. Although C1q itself displayed no DNase activity, it strongly augmented the activity of serum DNase I. Whereas an excess of recombinant DNase I degraded chromatin in the absence of C1q, efficient uptake of the predigested material by monocyte-derived phagocytes required the presence of C1q. These data show that C1q and DNase I cooperate in the degradation of chromatin from necrotic cells. Furthermore, C1q was found to be necessary for effective uptake of degraded chromatin by monocyte-derived phagocytes.Conclusion. C1q or DNase I deficiencies may precipitate autoimmunity in humans by a mechanism similar to that of other molecules that are involved in the safe, efficient, and rapid disposal of dying cells.

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C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and Cd91 Initiates Macropinocytosis and Uptake of Apoptotic Cells

Cited by 1,037 publications

References 124 publications

Mannose‐binding lectin engagement with late apoptotic and necrotic cells

Mannose‐binding lectin engagement with late apoptotic and necrotic cells

Genetically determined high serum levels of mannose-binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

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

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