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.