The role of neutrophil extracellular traps in hepatic immune homeostasis

Pérez Olivares, Laura (2023): The role of neutrophil extracellular traps in hepatic immune homeostasis. Dissertation, LMU München: Medizinische Fakultät

Abstract

The liver is a frontline immunological barrier tissue, an active detoxifying filter and the most important metabolic organ in human beings. The liver immune compartment is capable of detecting, capturing and clearing pathogens, pathogen-associated molecular patterns (PAMPs), gut-incoming antigens and diet-derived metabolites. Consequently, the hepatic immune compartment needs to ensure a delicate balance between tolerogenic and inflammatory responses, against non- and pathogenic insults, respectively. NETosis, a neutrophil-specific cell death program, is characterized by the release of web-like structures referred to as neutrophil extracellular traps (NETs). NETs are composed of extracellular DNA strands associated with modified histones and neutrophil granular proteins. NETs exert a key antimicrobial function that allows neutrophils to capture and kill pathogens. Here, we found that NET-like structures are present in murine immunological barrier tissues (e.g. spleen, lung, lymph nodes, liver) in the absence of pathology, likely supporting an alternative role of neutrophils and NETs during tissue homeostasis. In particular, NET-like structures emerged significantly during the night-time in the hepatic tissue. Absence of NET-like structures in different neutrophil-deficient knock-out mice, and their inhibition upon DNAse I or BB-Cl-Amidine treatment, confirmed the neutrophil-origin of the identified NETs and that their presence during tissue homeostasis helps maintaining a systemic anti-inflammatory condition. Homeostasis refers to the highly dynamic processes occurring within an organism internal environment in order to ensure a constant threshold of physiological parameters. Interestingly, mice are nocturnal creatures that have a night-associated active period, when they eat substantially more food compared to the diurnal phase and are exposed to an increased amount of potential insults. This brought up the idea of NETs being not just an inner circadian-regulated immunological function, but rather that food intake could work as an environmental entrainment cue for NET release. The NETosis dynamic profile in the liver was modified upon different dietary patterns, the diet´s nutritional composition and the chemical structure of the main fatty acid content of dietary fats. A diet high in fat and sugar induced the highest NETosis ratios, compared to diets with a low-fat content or fasted conditions. Fat-rich diets induce gut-permeability, intestinal dysbiosis and metabolic endotoxemia. NETs emerged as a key component of the hepatic immunological barrier system as sentinels against gut-derived PAMPs and DAMPs (reflected by a higher TLR2- and TLR4-night-associated activity), and as peacemakers within the low-profile pro-inflammatory scenario associated to postprandial conditions. Conditions gathering a higher and local hepatic presence of NETs at night were overall associated with a lower pro-inflammatory profile in the liver. Levels of IL-5 and IFN-γ (pro-fibrotic cytokines) were particularly augmented in the liver in absence of NETs. Altogether, our study spotlights NETs as key players in the maintenance of the hepatic tolerogenic and anti-inflammatory immune status and, ultimately, in the normal liver physiology.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: neutrophils, neutrophil extracellular traps, barrier tissues, hepatic tissue, immune homeostasis, circadian rythms, dietary patterns, PAMPs, immunosurveillance
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. März 2023
• 1. Bericht­erstatter:in: Söhnlein, Oliver