Complement and hypertension
Complement is an ancient part of the host defense machinery that, together with the contact and coagulation systems and the various branches of innate and adaptive immunity, helps to maintain barrier functions and protect against microbial invasion after injury. The role of complement is to detect, tag and eliminate pathogenic intruders with almost immediate reactivity (Figure 1) but sufficient specificity to avoid damaging host cells (Koenderman et al., 2014; Ricklin et al., 2018; Zipfel & Skerka, 2009). The membrane-attack complex (MAC) forms transmembrane channels, which disrupt the cell membrane of target cells, leading to cell lysis and death as shown in figure 1. In addition, complement activation in blood and the interstitial fluids leads to the mobilization of scavenger cells and the induction of the general inflammatory reaction, all events aimed at removing the perceived threat and restoring homeostasis (Merle et al., 2015).
While the field is still working on defining the exact molecular mechanisms driven by complement in circulation during hypertension and end organ failure, there may now be an additional complement-mediated angle to think about in this disease pathology: For many decades, complement was perceived to be a blood-borne immune system that was solely located in the intravascular space, with the entire spectrum of its components synthesized (with few exceptions) almost exclusively in the liver. Reports in the 1980s documented the presence of a functionally intact intracellular pool of the core components C3 and C4 within lymphocytes and other cell types (Lubbers et al., 2017), but the broader implications of these findings remained obscure. However, these observations hinted at an extra-hepatic importance of complement already early on. Renewed interest in the roles of complement generated by non-liver cells in the past years led to the identification of C3-mediated and C5-mediated activation and signaling events driven by cell intrinsic complement expression and function in intracellular, autocrine and paracrine fashions (Lalli et al., 2008; Liszewski et al., 2013; Strainic et al., 2008). Whilst the role of tonic intracellular complement activity seems to be sustaining immune cell homeostasis via regulation of cell metabolism (Kolev et al., 2015), cell autonomous complement is further activated during the sensing of danger, including cellular stress, pathogen presence etc. Such sensing then leads to increased production and activation of cell-intrinsic complement and the autocrine and paracrine stimulation of complement activation fragment receptors on immune cells to induce their respective effector activity (Ricklin et al., 2018). In fact, all immune cells express either all or a high number of complement receptors and regulators and can hence easily integrate incoming local complement activation signals.
As shown in figure 1 polymorphic neutrophils, monocyte/macrophages, dendritic cells (DCs) and human CD4+ and CD8+ T cells express anaphylatoxin receptors and complement regulators. DCs in the kidney can be identified by expression of MHC II and CD11c, a component of complement receptor 4. More than 90% of renal dendritic cells also express the CD11b, a component of complement receptor 3 (Gottschalk & Kurts, 2015). Further, B cells express complement receptors 1 and 2 (CR1/CR2) that engage for optimal antibody production (Gottschalk & Kurts, 2015). Follicular helper cells sample and retain antigen also in a complement-receptor-dependent fashion (Panneton et al., 2019). It is now undisputed that complement and its receptors are fine-tuning and shaping adaptive immune responses. Since the adaptive immune system plays an important role in arterial hypertension, it is feasible to now explore complement also a potential regulator of arterial hypertension via an innate and ‘adaptive immunity axis’. Therefore, as shown in figure 1 complement is engaged in three pathways inducing hypertension and hypertensive end organ damage: by itself, by influencing innate immune cells like PMNs and monocyte/macrophages as well as by fine-tuning cells like DCs, T and B cells of the adaptive immune system. Hypertensive end organ damage most likely starts with endothelial dysfunction and injury (Figure 1).
We will initially focus on the better-defined connections between complement and hypertension and speculate on possible new connections in the outlook section.