Diversity in neutrophil biology : from simple foot soldiers to versatile commanders of immunity in infectious diseases

Abstract

Pathogen clearance in infectious diseases strongly depends on a fine-tuned interplay between innate and adaptive immunity. Undoubtedly, neutrophils as first line defense against invading pathogens play a major role to recognize, phagocytose and kill the invaders. However, the diverse role of neutrophils under inflammatory conditions in infectious diseases has been largely ignored so far. In my PhD thesis, I addressed the implications of the versatile neutrophil functions in immunity encountering pathogenic microorganisms that cause infectious diseases. In particular, experimental approaches with human neutrophils from healthy individuals and from patients suffering from various infectious diseases and immunological disorders, respectively, were combined with a mouse model of Salmonella infection with the help of techniques such as flow cytometry, reverse transcription- polymerase chain reaction (RT-PCR) and proteomics to reveal the so far underestimated diversity in neutrophil function. We showed that “simple foot soldier” neutrophils are important for host defense against bacterial and fungal pathogens. With the help of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase (MPO), neutrophils are able to produce large amounts of reactive oxygen species (ROS) that are important for pathogen destruction. We could show that neutrophils from patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) have significantly impaired ROS production against Candida (C.) albicans and Aspergillus (A.) fumigatus. However, ROS can also cause detrimental damage in host tissues. We showed that MPO, one of the key enzymes in ROS production, has a protective role in the host by scavenging diffusible hydrogen peroxide (H2O2) at the Salmonella surface and converting it into highly reactive hypochlorite (HOCl) within a short reach. This sophisticated mechanism of MPO- to confine potential harmful molecules to the pathogen microenvironment- leads to both effective pathogen destruction and minimal collateral host tissue damage. Neutrophils as “versatile commanders” are unambiguously involved in the pathogenesis of sepsis, the dysregulated host response to infection. We could observe that neutrophils and monocytes accumulate neutral lipids during Salmonella infection and change their lipid metabolic program in sepsis comparable to atherosclerosis. Moreover, we identified a subset of antigen-presenting cell (APC)-like neutrophils with major histocompatibility complex (MHC) class II molecule expression, which could be induced under inflammatory conditions. The inflammatory environment triggers highly specific signaling pathways in neutrophils that orchestrate intracellular protein phosphorylation cascades, finally leading to the formation of the MHC class II enhanceosome. We could show that the MHC class II enhanceosome is responsible for the subsequent MHC class II expression on neutrophils and that targeting Janus kinase (JAK) 1/2 could be a promising therapeutic approach in sepsis to reach homeostasis. Overall, these data show that the immunological function of neutrophils in sepsis is highly versatile and goes far beyond simple pathogen destruction. Together, these data show that infectious disease control implies a specialized, but versatile immune system with diverse neutrophil functionality.