Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity

Abstract

Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.

HIV Tat causes synapse loss in a mouse model of HIV‐associated neurocognitive disorder that is independent of the classical complement cascade component C1q

“…In addition to promoting phagocytosis, complement activation results in the production of anaphylatoxins, C3a and C5a, that cause chemotaxis of immune cells and glia, promote proinflammatory polarization and cytokine production, and stimulate oxidative bursts (reviewed in Schraufstatter, Khaldoyanidi, & DiScipio, 2015;Thielens, Tedesco, Bohlson, Gaboriaud, & Tenner, 2017). C1q also has immunoregulatory properties that suppress proinflammatory cytokine production and limit inflammation when clearing apoptotic cells and debris, but how this anti-inflammatory effect is received by immune cells may depend on their differentiation state and the surrounding inflammatory milieu (Colonna, Parry, Panicker, & Elkon, 2016;Fraser, Laust, Nelson, & Tenner, 2009 that C1q is involved in synapse removal or clearance of cellular debris at the injection site early on, but that other "eat me" signals also exist that can fully compensate for the loss of C1q. The 7 days time point used for western blots was aimed at assessing synapse loss at an earlier time point, but it also leaves time for compensatory mechanisms to compensate for the loss of C1q.…”

C1q: A fresh look upon an old molecule

“…Studies over the last 15 years confirmed that C1q enhances phagocytosis of a variety of apoptotic cells by multiple cell types both in vitro and in vivo (reviewed in (Galvan et al, 2012a)). Interestingly, most recently Elkon and colleagues, using an inhibitor of C1s, demonstrated that C1q facilitates apoptotic cell engulfment independent of classical pathway activation (Colonna et al, 2016). …”

“…While there have been some studies suggesting the possibility of a direct C1q interaction with T cells, more definitive investigations are needed (reviewed in (Clarke and Tenner, 2014)). The recent confirmation of the predominant role of C1q (rather than C1 activation and C3b deposition) on clearance and immunosuppression of apoptotic cells should direct therapeutic intervention in SLE and other autoimmune diseases (Colonna et al, 2016). …”

Complement in removal of the dead – balancing inflammation

“…A recent study confirmed the important role of C1q as a bridging molecule between apoptotic cells and phagocytes and additionally pointed out the less studied role of C1q in controlling the phagocyte inflammatory status . C1q has previously been shown to promote immune tolerance and to resolve inflammation by modulating the cytokine release by phagocytes toward an immunomodulatory/anti‐inflammatory direction . Remarkably, C1q appears to have an inhibitory effect on inflammasome activation in macrophages .…”