Neutrophil-derived mediators in cardiometabolic inflammation

Abstract

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