Non-canonical complement and sensor system cross talks –
evolutionary clues
Innate immune sensor systems have traditionally been viewed as primary
protectors against infections. This view is now changing and it is
becoming broadly acknowledged that all innate immune sensors, including
the Toll-like receptors (TLRs) and inflammasomes are key to also
detecting and rectifying deviations from cell homeostasis – and
particularly impact on those that maintain cell physiology (Kolev &
Kemper, 2017; Prochnicki & Latz, 2017; Yiu et al., 2017). Blood
pressure control and host defense are such essential mechanisms of
homeostasis and it therefore not surprising that evolution incorporated
complement – among the TLRs and inflammasomes (McCarthy et al., 2014;
Pasqua et al., 2018) – as active participant in the regulation of blood
pressure. Infection can cause hypotension via fluid loss during fever,
tachypnea and diarrhea. Septicemia induces inflammation-related vascular
fluid losses. Thus, the risk of hypotension related to inflammation
might have favored selection of mechanisms that link immune and
complement activation to blood pressure increases for short-term
survival benefits. Such an evolutionary force may explain why important
antimicrobial effectors could have direct hypertensive effects by
promoting vasoconstriction or sodium retention (Wenzel et al., 2016).
First data suggest indeed that complement can directly activate the
renin-angiotensin system since Chen et al . showed just recently
that C3 binding to C3a upregulates renin transcription in vitro (Chen at
al. 2020b).
The importance of the ancient sensor systems in the regulation of cell
physiology became most apparent when their central roles in cell
metabolism were discovered. For example, in the case of complement, it
was found that low-level activation of human T cell intrinsic,
intracellular C3 into C3a and C3b by the ancient protease cathepsin L
(CTSL) leads to tonic lysosomal C3aR engagement. This, in turn, drives
basal mammalian target of rapamycin (mTOR) activity and sustains
homeostatic cell survival as shown in figure 1 (Liszewski et al., 2013).
During immune cell activation and cell movement into tissues,
intracellular C3 generation and activation is increased via LFA-1
mediated signals (Kolev et al., 2020) and autocrine engagement of the
C3aR and CD46 (a receptor/regulator for C3b) drives then nutrient influx
and metabolic programming (glycolysis, fatty acid metabolism and
oxidative phosphorylation) needed for immune cell effector function
(Arbore et al., 2018; Kolev et al., 2015). Importantly, intracellular
and/or cell-autonomous complement engages in a heavy crosstalk with the
NLRP3 inflammasome in immune cells to generate optimal and sustained
tissue immunity (Arbore et al., 2016). In consequence, reduced or
overactive intracellular complement contributes to the hypo- or
hyperactive immune cells responses observed in primary immunodeficiency,
in chronic infections and in autoimmunity, respectively (Arbore et al.,
2017; West & Kemper, 2019). The finding that intracellular
cell-autonomous complement is key to immune cell function now suggests
that this could be a new avenue to explore in hypertension: it is
possible that intracellular complement perturbation contributes the
aberrant innate and adaptive immune cell behavior observed in this
disease state (Figures 1 and 4). Indeed, changes in metabolic pathways
are being functionally connected with pulmonary arterial hypertension
(Ryan & Archer, 2015). Moreover, given that we have so far observed an
intracellular complement in all cells analyzed, it may be worthy to
explore a role for intracellular complement in the direct regulation of
endothelial cell metabolism during hypertension (Cao et al., 2019).
Similarly, a ‘second look’ into the proteases that allow for
intracellular non-canonical complement activation may also be
informative. For example, a novel functional polymorphism in theCTSL gene alters blood pressure (Mbewe-Campbell et al., 2012) and
changes in the CTSL gene promotor have been connected with hypertension
(Chen et al., 2015) – potential changes, however, in C3 processing
within the endothelium are unexplored.