Neutrophils during acute inflammation: Trojan horses or elite defenders?

Abstract

Immunity can be described as the ability of the human body to ward off invading pathogens or toxins by the action of leukocytes or products synthesized by these white blood cells. Under homeostatic conditions the vast majority of all circulating leukocytes are polymorphonuclear cells, or neutrophils, which belong to the group of innate immune cells and form the first line of defence. During homeostasis these cells act as surveillance cells in the circulation whilst low number of neutrophils are present in the peripheral tissues. Upon disturbance of the homeostatic state, either by tissue-injury or by invasion of pathogens, large numbers of neutrophils are mobilized from the bone marrow to the bloodstream in order to perform their action in peripheral tissue. A downside to a high number of activated neutrophils at sites of inflammation is matched in some circumstances by a capacity for host tissue destruction resulting in pro-inflammatory complications such as the acute respiratory syndrome. A tailored response, without under or over-activity is therefore of crucial importance in order to successfully clear the harmful threats whilst preventing excessive tissue damage and organ failure. In recent years it was shown that several subtypes of neutrophils are present in the bloodstream during acute inflammation. This thesis revolves around the question whether circulating neutrophils during acute inflammation, in particular after bacterial invasion, are favourable or unhelpful for the outcome of a patient. The first step in answering this question is to establish the exact function of neutrophils during acute inflammation. In this thesis a novel experimental setup is described in which a composite of neutrophil antimicrobial functions can be simultaneously tested. This setup is used to test the antimicrobial functions of neutrophils from healthy volunteers challenged with human endotoxemia, thereby mimicking acute inflammation in a controlled setting. Large differences in anti-bacterial capacity were observerd between neutrophil subsets. These studies are supplemented with data from neutrophils derived from children affected with chronic granulomatous disease and mechanisms behind defective anti-bacterial capacity are explored. After outlining specific anti-microbial functions by the different subsets of neutrophils, the distribution pattern of these cells in the first 2 weeks in patients with severe traumatic injury are studied and it was shown that one week after trauma a subset of neutrophils prevails which is characterized by a very poor capacity to cope with bacteria. These findings might account for the increased susceptibility to infections in this group of patients.