Title: Neutrophils in immune defence and disease
Funder: The Francis Crick Institute

Abstract: Neutrophils are essential immune phagocytes. They are rapidly recruited to sites of infection and engage pathogens via degranulation, phagocytosis and the release of extracellular web-like structures called neutrophil extracellular traps (NETs). NETs are composed of decondensed chromatin and antimicrobial proteins that trap and kill microbes extracellularly but their overall significance for immune defense remained unclear. Furthermore, NETs are linked to immune pathology and human disease. We are investigating the mechanisms that regulate neutrophil responses to infection, how these responses clear microbes effectively and how they are involved in inflammatory disease. Traditionally, neutrophils were thought to play negligible regulatory roles and implement their antimicrobial strategies indiscriminately. Using biochemical, cell biological and in vivo mouse models we have shown that neutrophils shape inflammation and adapt their antimicrobial strategies according to the size of invading microbes. The immune mechanisms that combat large pathogens had previously been poorly understood. We found that neutrophils sense microbe size and selectively release neutrophil extracellular traps (NETs) to combat large pathogens, such as fungal filaments. Moreover, NET release is confined to the clearance of large microbes which limits NET-mediated pathology when microbes are small enough to be killed intracellularly. In addition, neutrophils employ reactive oxygen species (ROS) as sensors of microbe size to adjust their recruitment and organization according to microbe size, compensating for differences in the stoichiometry of host-pathogen interactions. Our findings uncovered distinct inflammatory programs that are tuned to combat microbes of different size. We showed for the first time that cells are able to sense the cellular localization of ROS and employ ROS as universal sensors of microbe size. This ability enables neutrophils to tune inflammation and adjust their recruitment and clustering to the size of microbes they encounter. Our data suggest that human inflammatory conditions can be caused by deficiency in ROS-mediated microbe size sensing mechanisms. These concepts can be exploited therapeutically to treat hyper-inflammatory disease. In addition, neutrophils regulate sterile inflammation and atherosclerosis via the release of NETs. The signals that drive the transcription of pro-inflammatory cytokines under sterile conditions where bacterial activators are absent, remained unclear. In atherosclerosis, cholesterol crystals form in the vasculature and induce the key pro-inflammatory cytokine IL-1β. We found that cholesterol crystals trigger NET release in atherosclerotic lesions in response. These NETs “license” macrophages for inflammation by inducing the transcription of IL-1 and IL-6 cytokines driving the recruitment of myeloid cells to atheromas. This paradigm explains how in the absence of microbial priming cues, endogenous danger signals such as cholesterol crystals are sufficient to drive inflammatory disease. Furthermore, this work uncovered new potential targets for the development of treatments for atherosclerosis and other inflammatory conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM