Mannose‐binding lectin engagement with late apoptotic and necrotic cells

Abstract

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.

Mannose-Binding Lectin-Deficient Mice Display Defective Apoptotic Cell Clearance but No Autoimmune Phenotype

“…Interestingly, not only do both C1q and MBL cluster on apoptotic cells as death progresses, but they also both contribute to clearance in vivo. MBL and C1q have been shown to recognize distinct and only partially overlapping surface ligands on dying cells (26), and it is likely, therefore, that the similarities in the in vivo phenotype of the C1qA Ϫ/Ϫ and MBL null animals is a consequence of their shared ability to trigger a common pathway or mechanism of uptake. This hypothesis is in keeping with the observed similarity in the extent of the defect in apoptotic cell clearance in the peritoneum of both C1q and MBL null animals.…”

“…An important difference between C1q and MBL is the ability of C1q to trigger complement deposition on the surface of the apoptotic cell (26) and to recognize Ab-opsonized apoptotic cells and immune complexes. It is possible that it is specifically failed clearance of Ab opsonized apoptotic cells, and associated proinflammatory responses, that renders apoptotic cells more immunogenic in the context of C1q deficiency.…”

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

“…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).…”

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

“…Since PS is also exposed on necrotic cells, it was not surprising that PS-dependent mechanisms contribute to the uptake process of necrotic cells as well (24,25). In addition, mannose-binding lectin (MBL) and pulmonary SP-A and SP-D bind to late apoptotic (i.e., secondary necrotic) and primary necrotic cells and facilitate their engulfment (13,26).…”