Atherosclerotic plaque destabilization in Mice: A comparative study

Atherosclerosis-Associated diseases are the main cause ofmortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions thatmay become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-Threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animalmodelsmimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models

Neutrophil-derived mediators in cardiometabolic inflammation

The immune system is a complicated system that helps to protect the body from alien pathogens and damage. The workers of this system are the white blood cells, a variety of immune cells that were each thought to have specialized tasks and abilities. However, extensive research has shown that these specialized cells can be more plastic and have broader capacities than previously imagined. Among these immune cells, the most numerous circulating is the human neutrophil. Previously, these polymorph nuclear granulocytes were mainly thought to be involved in the defence against pathogens. However, recent studies indicated additional roles during sterile and chronic inflammation. This thesis describes a journey, aimed to further understand how neutrophils participate in the chronic inflammation that lays at the basis of cardiometabolic disorders, focusing mainly on obesity and atherosclerosis. The main finding are: The granule protein cathelicidin can mediate obesity induced adipose tissue inflammation through the recruitment of immune cells into the inflamed tissue. Inhibition of neutrophil extracellular trap formation during diet induced obesity does not reduce disease severity. Neutrophils can destabilize atherosclerotic plaques by secretion of neutrophil extracellular traps on top of stabilizing smooth muscle cells. Moreover, these neutrophil extracellular traps contain cytotoxic histones that can perforate smooth muscle cells, resulting in a novel receptor independent lytic form of cell death and subsequent thinning of the fibrous cap. This lytic cell death is not cell specific and might play a role in any acute or chronic inflammation fostered by non-programmed or non-resolved cell death

Neutrophil-derived mediators in cardiometabolic inflammation

The immune system is a complicated system that helps to protect the body from alien pathogens and damage. The workers of this system are the white blood cells, a variety of immune cells that were each thought to have specialized tasks and abilities. However, extensive research has shown that these specialized cells can be more plastic and have broader capacities than previously imagined. Among these immune cells, the most numerous circulating is the human neutrophil. Previously, these polymorph nuclear granulocytes were mainly thought to be involved in the defence against pathogens. However, recent studies indicated additional roles during sterile and chronic inflammation. This thesis describes a journey, aimed to further understand how neutrophils participate in the chronic inflammation that lays at the basis of cardiometabolic disorders, focusing mainly on obesity and atherosclerosis. The main finding are: The granule protein cathelicidin can mediate obesity induced adipose tissue inflammation through the recruitment of immune cells into the inflamed tissue. Inhibition of neutrophil extracellular trap formation during diet induced obesity does not reduce disease severity. Neutrophils can destabilize atherosclerotic plaques by secretion of neutrophil extracellular traps on top of stabilizing smooth muscle cells. Moreover, these neutrophil extracellular traps contain cytotoxic histones that can perforate smooth muscle cells, resulting in a novel receptor independent lytic form of cell death and subsequent thinning of the fibrous cap. This lytic cell death is not cell specific and might play a role in any acute or chronic inflammation fostered by non-programmed or non-resolved cell death

Methanotrophy by a Mycobacterium species that dominates a cave microbial ecosystem

So far, only members of the bacterial phyla Proteobacteria and Verrucomicrobia are known to grow methanotrophically under aerobic conditions. Here we report that this metabolic trait is also observed within the Actinobacteria. We enriched and cultivated a methanotrophic Mycobacterium from an extremely acidic biofilm growing on a cave wall at a gaseous chemocline interface between volcanic gases and the Earth’s atmosphere. This Mycobacterium, for which we propose the name Candidatus Mycobacterium methanotrophicum, is closely related to well-known obligate pathogens such as M. tuberculosis and M. leprae. Genomic and proteomic analyses revealed that Candidatus M. methanotrophicum expresses a full suite of enzymes required for aerobic growth on methane, including a soluble methane monooxygenase that catalyses the hydroxylation of methane to methanol and enzymes involved in formaldehyde fixation via the ribulose monophosphate pathway. Growth experiments combined with stable isotope probing using 13C-labelled methane confirmed that Candidatus M. methanotrophicum can grow on methane as a sole carbon and energy source. A broader survey based on 16S metabarcoding suggests that species closely related to Candidatus M. methanotrophicum may be abundant in low-pH, high-methane environments

Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis

Aims Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear.Methods and results Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques.Conclusion Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.[GRAPHICS]This study provides novel mechanistic insights into how acutemental stress fuels vascular inflammation and promotes plaque rupture. EC, endothelial cells; HPA, hypothalamic-pituitary-adrenal axis; MACS, macrophages; SAM, sympathetic-adrenal-medullary axis

Neutrophils as protagonists and targets in chronic inflammation

Traditionally, neutrophils have been acknowledged to be the first immune cells that are recruited to an inflamed tissue and have mainly been considered in the context of acute inflammation. By contrast, their importance during chronic inflammation has been studied in less depth. This Review aims to summarize our current understanding of the roles of neutrophils in chronic inflammation, with a focus on how they communicate with other immune and non-immune cells within tissues. We also scrutinize the roles of neutrophils in wound healing and the resolution of inflammation, and finally, we outline emerging therapeutic strategies that target neutrophils.</p