Despite considerable progress in its management and therapy, cardiovascular disease
remains the major cause of death in the Western world.[1] The causal factor driving most of these conditions is atherosclerosis. To develop
more effective strategies for the prevention and treatment of arterial disease, a
better understanding of the pathogenesis and progression of atherosclerosis is crucial.
A group of outstanding basic and clinical scientists from different research campuses
in Munich, Germany, has joined forces in a unique multidisciplinary network entitled
Collaborative Research Center (CRC) 1123 “Atherosclerosis—Mechanisms and Networks
of Novel Therapeutic Targets.” The long-standing goal of the CRC 1123 is to provide
an in-depth mechanistic understanding of molecular networks in atherogenesis, progression
and atherothrombosis. This theme issue presents some of the novel immunotherapeutic
targets that are currently studied by the CRC 1123 network as potential future treatment
for atherosclerosis in a collection of five review articles.
To start with, Kaltner and Gabius highlight the relevance of cell surface glycans,
which are recognized by specific receptors called lectins, as biological signals for
haemostasis, platelet functionality and inflammation.[2] For example, the circulatory lifespan of platelets is shortened during systemic
bacterial infection due to the activity of bacterial sialidases on cell surface glycans.
Desialylated platelets can be removed from the circulation by specific hepatic lectin
receptors, which is also a relevant mechanism during sepsis to limit the severity
of disseminated intravascular coagulation.[3] The variability of the glycan structures composed of sugars and glycosidic bonds
on the cell surface binding to a large network of lectin receptors may translate into
very fine-tuned intracellular effects. Initially widely ignored, it is increasingly
recognized that the carbohydrate structures represent specific ‘codes’ with biological
specificity that are defined by the variability of their sugars and linkage position.
On the receptor side, the growing network of lectins involved in the biological processes
of platelet activation and inflammation comprises selectins and many other C-type
lectins, galectins and siglecs.[2]
The following two reviews[4]
[5] discuss the emerging family of atypical chemokines (ACKs). Macrophage migration-inhibitory
factor (MIF) is an inflammatory cytokine that is classified as ACK, because it exhibits
chemotactic activity and binds to classical chemokine receptors CXCR2 and CXCR4, but
lacks the typical chemokine-fold and conserved N-terminal cysteines of classical chemokines.[4] MIF is up-regulated in human atherosclerotic lesions and promotes atherogenic leukocyte
recruitment and lesional inflammation in experimental models via CXCR2 and CXCR4 as
well as CD74 (also known as human leukocyte antigen class II histocompatibility antigen
gamma chain).[4] Although inhibitors of MIF signalling are already in clinical development for specific
conditions such as metastatic colorectal cancer,[6] the possible therapeutic targeting of MIF in cardiovascular disease is challenging
due to stage-dependent differential effects. Other ACKs bind to ACK receptors (ACKRs),
which in contrast to the well-known classical CC- and CXC-type chemokines, do not
elicit a G-protein-dependent signalling response upon binding to their cognate receptors.[5] While the implication and therapeutic targeting of classical chemokine receptors
in cardiovascular disease has been extensively studied during the last two decades,
the pathophysiological roles of ACKRs in this context is still poorly understood.
In view of developing more efficient therapeutic drugs for cardiovascular disease,
ACKRs are of particular interest as they are major regulators of chemokine availability
and signalling. Despite their inability to bind G proteins, ACKRs can internalize,
scavenge, transport or present chemokines and thus regulate the bioavailability of
chemokines and thereby chemokine signalling via classical receptors.[5]
In the next contribution, Van Avondt et al provide an update on growing experimental
evidence for a causal relationship between neutrophil extracellular traps (NETs) and
atherothrombosis.[7] NETs have been linked to acute coronary events, including ST elevation myocardial
infarction in humans, as well as plaque formation and superficial erosion in experimental
models. The strategies used to clarify the pathophysiological role of NETs and mechanisms
triggering NET release in atherosclerosis and thrombosis involve DNase injection or
transgenic mouse models that fail to induce NETs. Although it is tempting to suggest
that interfering with NET formation may result in multiple beneficial effects in cardiovascular
disease patients, more research is needed to better understand the molecular mechanisms
of NET activation as well as their detrimental and possibly beneficial functions in
acute and chronic cardiovascular conditions.
The last review article[8] adds metabolic disorders such as obesity as additional complication in cardiovascular
disease, which is a common co-morbidity that has risen dramatically over the last
four decades.[9] Overactive endocannabinoid signalling is a common feature of obesity and atherosclerosis,
which involves an up-regulation of endogenous lipid mediators (endocannabinoids) derived
from membrane phospholipids that bind to central and peripheral cannabinoid receptors.
Enhanced endocannabinoid signalling affects atherosclerosis by modulating vascular
inflammation, leukocyte recruitment and cholesterol metabolism. In addition, enhanced
CB1 signalling promotes metabolic disorders such as obesity and dyslipidaemia, which
further promotes the chronic inflammatory state underlying atherosclerosis.[8]
In summary, this theme issue highlights some emerging regulators and their interactions
in the complex pathogenesis of atherosclerosis, which deserve further attention. The
recent findings of the CANTOS trial have clearly proven that inflammation is a key
driver of atherosclerosis and that targeting inflammation improves cardiovascular
disease outcomes.[10] Nevertheless, innovative anti-inflammatory therapies are warranted that more efficiently
reduce cardiovascular disease and mortality, while limiting side effects such as enhanced
susceptibility to infection. Among the potential targets presented in the five review
articles, interfering with chemokine signalling may be most promising and advanced.
In light of the positive CANTOS outcome, the CRC 1123 will continue its mission to
provide an in-depth mechanistic understanding of the molecular networks underlying
atherogenesis to identify novel therapeutic targets. To this end, we will extend the
scope of the theme issue series in a subsequent second part to therapeutic targeting
of platelets in atherothrombosis, highlighting novel Bruton's tyrosine kinase inhibitors,
to targeting mononuclear phagocytes, for example, focusing on regulatory effects of
long non-coding ribonucleic acids (RNAs) and micro-RNAs, and to exploring novel imaging
modalities for therapeutic translation.
