Abstract
Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested ex vivo. In Menkes disease mice, the in vivo effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by ex vivo studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.
Highlights
The capacity to cast neutrophil extracellular traps (NETs) by neutrophils was described 15 years ago, yet not all aspects or mechanisms of their release were revealed far [1]
To detect NETs in the liver, mice were injected with fluorescent Sytox green to stain extracellular DNA (extDNA) and Alexa Fluor 647 labeled antibodies directed against neutrophil elastase
Endotoxemia occurs in many patients with sepsis, and in many clinical settings that are non-infectious in nature
Summary
The capacity to cast neutrophil extracellular traps (NETs) by neutrophils was described 15 years ago, yet not all aspects or mechanisms of their release were revealed far [1]. While originally NETs were believed to be beneficial for the host defense via their capacity to capture and immobilize pathogens [1, 6], it was subsequently recognized that they can cause bystander damage or contribute to disease outbreak or relapses [7,8,9]. This “Dr Jekyll and Mr Hyde phenotype” can be attributed to early and late stages of inflammation, respectively. There are multiple conditions in which liver is strongly affected, and some of them are connected with excess/deficiency of microelements [13,14,15,16]
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