2.1 MBL and C1q
MBL and C1q are two soluble pattern recognition molecules in complement classical pathway (CP) and lectin pathway (LP). Report found that C1q widely distributed in decidual stroma and the vessel wall of the spiral arteries 25. C1q is synthesized by extravillous trophoblasts, decidua endothelial cells and macrophages in placenta26. In addition to local expression of C1q, excessive complement activation leads to increased local recruitment of C1q from the blood circulation into the placenta, especially in areas of fibrinoid necrosis in maternal decidua 27.
MBL and C1q recognize and bind to a variety of damage-associated molecular patterns (DAMPs) like phosphatidylserine, mitochondrial membranes, histones, DNA, Annexins 2 (A2) and A5 on apoptotic cell28. C1q comprise of N-terminal domain (also called collagen-like domain) and a C-terminal globular domain (gC1q)29. Immobilized C1q can enhance FcγR-mediated phagocytosis of either immobilized or soluble immune-complex (IC), antibody or complement-opsonized targets 30,31. C1q can trigger an immediate response to enhance their phagocytosis. Moreover, gene expression profiles found that multiple pro-phagocytic genes were upregulated in C1q treated bone marrow derived macrophages (BMDM) in mice. C1q binds to apoptotic cell 32 by the globular head region 33. Accumulated evidence confirmed that C1q can enhance phagocytosis of apoptotic cells both in vitro and vivo (reviewed in (Galvan et al., 2012) 34). C1q and MBL have similar collagen-like domains. Experiments also found that MBL can facilitate apoptotic cells clearance. The expression of MBL is increased on the apoptotic cell35. Low MBL levels can result in impaired apoptotic cell clearance36. Aside from direct recognition and removal of apoptotic cells by acting as an opsonin, C1q and MBL also play an indirect role in apoptotic cell clearance by C3 cleavage fragments. The active C1 complex cleaves the following components C4 and C2, resulting in the assembly of the C3 convertase (C4b2a) and C3b/iC3b production disposition on targets, which are strong opsonins for phagocytosis. Increased apoptotic cells were detected in lymph nodes and other tissues in C1q−/−mouse37-38.
In addition to promoting apoptotic phagocytosis, C1q/MBL is also involved in inducing immune tolerance thus help silent removal of dying cell. When binding to apoptotic cells, C1q maintain dendritic cells (DCs) in immune tolerance state through interact with gC1qR39 and suppresses Th17 and Th1 cell proliferation40,41. C1q−/− mice were detected to produce elevated levels of IL-12p40 compared to wild type mice42. At the same time, immobilized C1q can increase the production of IL-10 known as anti-inflammatory mediators 43,44. C1q/gC1qR interaction on DCs or macrophages can negatively regulate IL-12p70 production through activating the phosphoinositide 3-kinase (PI3K) pathway 45. C1q also inhibits immune complex induced IFN-α production in pDCs 46. These evidence reinforced that C1q and its receptor complex could regulate DC induced inflammation47.
C1q attracted on apoptotic cells bind to C1qRs on macrophage to suppress IL-10, IL-27, IL-33, and IL-37 secretion and inhibit inflammasome activation. At the same time, it can also increase the level of negative regulators 40. Another experiment indicated that C1q mediated apoptotic cells clearance procedure can increase the expression of Programmed death-ligand 1 (PDL-1) and PDL-2 and decrease the expression of CD40 on macrophages or DCs surface 41. It induces elevated regulatory cell (Treg) differentiation and anti-inflammatory cytokines production, such as TGF-β, IL-10, IL-37, IL-27 and Prostaglandin E2 (PGE2), and lead to immune tolerance. In addition, C1q opsonization the phagocytosis of apoptotic cells and promote the expression of PDL-2 and suppress the expression of CD86 on DCs surface. It largely slow down the antigen presenting procedure and immunogenic efficiency, and ubsequently, it inhibits Th1 and Th17 proliferation (Figure 3). In all, C1q is critical for the silent clearance of apoptotic cells in and non-immunogenic state41.