Figure 4: C3b/CR2 interaction on red cell participate in immune complex (IC) clearance. CR2 is expressed on the surface of red blood cells. C3b can bind to IC and attach to the surface of red cells through CR2. With the blood flow, it enters the spleen and liver to be finally degraded. This is the main way for IC clearance. It is important for immune tolerance induction.
CR3 was once considered to be one of the pro-inflammatory receptors in innate immune system. Interestingly, the clear anti-inflammatory and immunoregulatory role of CR3 under certain circumstances has been widely identified 101. iC3b/CR3 mediated apoptotic cells clearance procedure can induce an anti-inflammatory response. iC3b/CR3 interaction inhibit TLR/nuclear factor-κB (NFκB) pathway to inhibit pro-inflammatory cytokines (such as IL-1, IL-6 and IL-12) secretion by macrophages and dendritic cells 102,102-105. It can also inhibit monocyte-derived DCs (Mo-DCs) differentiation through stimulating IL-10 and TNF-α production 106, and subsequently inhibits allogeneic CD4+ T cell proliferation through mitogen-activated protein kinase (MAPK) signaling pathway107. iC3b/CR3 downregulate the expression of costimulatory molecules (major histocompatibility complex) and MHC class II antigens on the phagocytic cells thus suppress further activation of adaptive T cell response 103. In addition, C3b/iC3b interact with the CRIg expressed on human DCs and inducing T cell stay in silent 104,105. CR3 also express in NK cell and serve as a maturation mark on it 108,109. C3 lysate have been shown to play a negative regulatory role in IFN-γ production and cell killing activity in NK cells 110,111. CR3/iC3b interact on DCs cell and inhibit IL-6, IL-23 and IL-1β secretion to restrain differentiation and proliferation of Th17 cells112. In line with this, mice with CR3 deficiency in antigen presenting cells (APC) have increased Th17 cell level and disrupted peripheral tolerance 113. (Figure 4)
A polymorphism of rs1143679 ITGAM encodes the variant alpha subunit of CR3 (R77H protein) and it weaken the adherence ability of iC3b then impair iC3b-dependent phagocytosis. R77H gene variant is associated with increased susceptibility to both SLE and PE114,115. CR1-CR4 are all receptors for iC3b mediated phagocytosis. It has been also reported that women with any protein deficiency in anyone of CR1-4 has a higher susceptibility to both PE and SLE 52.
C3 with its split products (C3b, iC3b, C3d) were detected in high level in placenta, it is worth noting that C3 is essential for pregnancy maintenance in mice. C3 ablation can increase fetal re-absorption rate and decrease conception rate in mice. The fetal and placental weights of C3-knockout mice group were lower than the control group116. In pregnancy mice model, CR3/iC3b interaction induce an elevated local anti-inflammatory cytokine expression (like IL-10 and TGF-β1) at the maternal-fetal interface 117. IL-10 and TGF-β1 are typical anti-inflammatory cytokines in suppressing T-cell activation and differentiation 118.