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.