Anaphylatoxin receptors
In addition to CD46 and VSIG4, the complement anaphylatoxin receptors for C3a and C5a, C3aR and C5aR, have also been implicated in regulating autophagy (H. Nguyen et al., 2018). Whereas CD46 appears to stimulate autophagy in tested cell types, C3aR and C5aR seem to inhibit macroautophagy-dependent breakdown of damaged mitochondria, a process known as mitophagy. C3a and C5a production are thought to stimulate survival and activation of graft-derived dendritic cells (DCs) in graft versus host disease (GVHD) (Cravedi et al., 2013), and authors found that donor DCs from C3aR-/-/C5aR-/-mice were less able to mediate GVHD in recipient mice (H. Nguyen et al., 2018). The knockout DCs had a higher turnover of precursors of ceramides, lipids that cause mitochondrial membrane damage and induce mitophagy(Sentelle et al., 2012). Knockout DCs had higher levels of mitochondrial proton leakage, a sign of mitochondrial membrane damage, and higher colocalisation of mitochondria with acidic lysosomal compartments, as well as higher levels of LC3-II. This indicates increased autophagic turnover, with the implication that damaged mitochondria were being removed by autophagy, a process known as mitophagy. In addition, administration of C3aR/C5aR antagonists replicated the protective outcome of C3aR/C5aR knockout, whereas the protective effect of knockout DC transplantation was reversed by pre-incubation with the autophagy inhibitor chloroquine. Although the finding that C3aR-/-/C5aR-/- immune cells are less able to mediate GVHD is entirely consistent with the known role of these receptors in immune cell activation and inflammation, this paper highlights a downstream role of autophagy inhibition after anaphylatoxin exposure in DCs. In this case, it seemed to be due to an alteration in lipid metabolism, which also fits into current understanding of the importance of metabolism (O’Neill, Kishton, & Rathmell, 2016) and in particular, the influence of complement signaling on metabolism (Kolev & Kemper, 2017), on the outcomes of immune cell activation.
Contrasting results were however described for C5aR in a paper showing that C5a can induce, rather than inhibit, autophagy in lung alveolar macrophages (Hu et al., 2014). Acute lung injury can be induced by ischaemia reperfusion (IR) injuries (de Perrot, Liu, Waddell, & Keshavjee, 2003), in which complement plays a pathological role (Keshavjee, Davis, Zamora, de Perrot, & Patterson, 2005; Naka, Marsh, Scesney, Oz, & Pinsky, 1997; Pierre et al., 1998). IR led to production of C5a in the lung bronchoalveolar lavage fluid, and administration of neutralizing anti-C5a antibody before injury improved pathological outcome (Hu et al., 2014). Alveolar macrophages from IR but not control mice had increased levels of LC3-II, indicating autophagy induction, and this was reversed by C5a neutralization. Autophagy activation was linked to degradation of Bcl-2, a well-known regulator of apoptosis. However, Bcl-2 also interacts with Beclin 1, inhibiting Beclin 1-dependent macroautophagy (Pattingre et al., 2005). Consequently, a reduction in Bcl-2 in lung alveolar macrophages of mice with IR injury resulted in activation of Beclin 1, demonstrating a cross-talk between complement signaling, apoptosis and autophagy pathways.