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.