Moreover, the gram-negative bacteria subvert the complement system to foster bacterial survival. C5b to form the MAC, which is a pore with cytolytic properties. At its final configuration, the MAC is composed of one copy of C5b, C6, C7, and C8 and up to 18 copies of C9, which constitute the bulk of the MAC pore (Mller-Eberhard, 1986; Merle BRL-15572 et al., 2015). The lectin pathway differs from the classical mainly because it is driven by mannose-binding lectin (MBL) and ficolins (Figure 1). Analogously to C1q, they bind to antigens to initiate the complement cascade, but BRL-15572 in this case, the antigens are carbohydrates such as mannose, glucose and N-acetyl-glucosamine (Holers, 2014; Merle et al., 2015). Binding of MBL to sugars on microbial membranes leads to TM4SF18 activation of MBL-associated serum proteases (MASPs) 1 and 2, which structurally and functionally similar to C1r and C1s, will initiate the cleavage of C4 and C2 to form the C3 convertase and unleash the complement cascade. Open in a separate window Figure 1 Schematic representation of the human complement system, which possesses three main pathways: the classical, the lectin and the alternative pathway. Scissors indicate proteolytic cleavage. FB, Factor B; FD, Factor D; MAC, membrane attack complex; MASP, MBL-associated serum protease; MBL, mannose-binding lectin. The complement cascade can also be initiated spontaneously by C3, the so-called alternative pathway (Figure 1). In the fluid phase, C3 can undergo spontaneous low-rate hydrolysis, or tick-over, to yield C3(H2O) (Holers, 2014; Hajishengallis et al., 2017). This form can bind Factor B, which when cleaved by the protease Factor D, produces a fluid-phase C3 convertase [C3(H2O)Bb]. This enzyme produces C3b in solution, which may deposit on nearby surfaces and complex with more Factor B, forming the C3 convertase of the alternative pathway (C3bBb). It is important to mention that this cascade is short-lived and insufficient to promote full complement activation. For that, the alternative pathway requires properdin, a phagocyte-derived protein that stabilizes C3bBb and allows it to cleave C3 for long enough to enter the amplification phase of complement activation. Interestingly, the alternative pathway does not require antibodies for initiation, however, the presence of antibodies, polysaccharides, lipopolysaccharides (LPS), gas bubbles, heme, BRL-15572 and properdin are all known to facilitate its activation. Moreover, the alternative pathway contributes to the full activation of complement via all pathways BRL-15572 (e.g. classical and lectin) by providing an amplification loop, in which deposited C3b continuously forms new C3 convertases by binding to Factor B. This dramatically increases the cascade activity and is associated to its effects BasophilsEosinophilsMonocytesMast cellsActivated T-lymphocytesTonsil-derived B-lymphocytesChemotaxis of mast cells, eosinophils and monocytes/macrophages (Daffern et al., 1995; Hartmann et al., 1997; Zwirner et al., 1998)Induction of ROS production in neutrophils (Elsner et al., 1994)No (or inhibition of) chemotaxis of neutrophils (Daffern et al., 1995; Wu et al., 2013)Retention of hematopoietic stem cells in the bone marrow (Reca et al., 2003; Ratajczak et al., 2004)Leukocyte recruitment to the brain (Wu et al., 2016; Crider et al., 2018)Regeneration of skeletal muscle and hepatic tissue (Strey et al., 2003; Markiewski et al., 2004; Zhang et al., 2017)C5aRC5aR1C5aNeutrophilsMonocytes/macrophages Dendritic cellsT-lymphocytesB-lymphocytesMast cellsChemotaxis of neutrophils, monocytes, dendritic cells, T- and B-lymphocytes (Morgan et al., 1993; Sozzani et al., 1995; Nataf et al., 1999; Ottonello et al., 1999)Degranulation of neutrophils (Morgan et al., 1993)Induction of ROS production in neutrophils (Sacks et al., 1978)Cytokine production in monocytes (Morgan et al., 1993)Mast cell histamine release (Johnson et al., 1975; Freder et al., 1995)Liver regeneration (Mastellos et al., 2001; Daveau et al., 2004; Marshall et al., 2014)C5L2C5aR2C5aImmature dendritic cellsGranulocytes (Myeloid immune cells)T cell subsetsImmune suppressing and immune activating functions due to regulation of C5aR activation and signaling (Li et al., 2019)CR1CD35C3b/C4b receptorC1qC3bC4biC3bMBLErythrocytesMonocytes/macrophagesGranulocytesB-lymphocytesCD4+ T-lymphocytesFDCsGlomerular podocytesImmune regulatory role (Iida and Nussenzweig, 1981; Masaki et al., 1992)Immune-complex clearance (Cornacoff et al., 1983)Phagocytosis (F?llman et al., 1993)CRIgVSIG4/B7 family-Z39IgC3bC3ciC3bTissue-resident macrophages MDDCsComplement-mediated phagocytosis (Wiesmann et al., 2006)Immune regulatory role (Vogt et al., 2006; Munawara et al., 2019)CR2CD21iC3bC3dgC3dgp350/220 (EBV)CD23Interferon-alphaB-lymphocytesFDCsT-lymphocytes Epithelial cellsLowering B-lymphocyte activation threshold (Carter and Fearon, 1992)Retention of C3-opsonized antigens (Reynes et al., 1985)Promotion of B-lymphocyte class switching and IgE production (Aubry et al., 1992)EBV cell entry (Tanner et al., 1987)CR3Mac-1CD11b/CD18 Integrin M2ICAM-1ICAM-2FibrinogeniC3bCollagenFactor XNIFNeutrophils Monocytes/macrophages Dendritic cellsNK cells Activated lymphocytesLeukocyte extravasation (Dustin and.
