Neutrophil intrinsic and extrinsic regulation of NETosis in health and disease

HighlightsRelease of neutrophil extracellular traps (NETs) by neutrophils is regulated by neutrophil-intrinsic and -extrinsic factors and pathways.Modifiers of histones play fundamental roles in driving NETosis. For example, histone deacetylation by class I and class IIb histone deacetylases (HDACs) is required to allow histone H3 citrullination by the enzyme PAD4.Regulation of gasdermin D (GSDMD) activation has been recently identified as a key process that controls the permeability of the nuclear, plasma, and granule membranes, thus allowing NET release.Metabolic pathways that regulate glycolysis and energy supply are tightly linked to the capacity of neutrophils to produce NETs.Macrophages work as either positive or negative regulators of NETosis.Platelets are major drivers of NETosis and platelet–neutrophil complexes (PNCs) control an inflammatory feedback loop that needs to be tightly regulated to avoid excessive NET release and to prevent thrombosis.Multiple exogenous and endogenous factors control the capacity of platelets to interact with neutrophils and to form PNCs. Among these factors, nuclear factor of activated T cells (NFAT) expressed by platelets has been shown to dampen platelet activation and induction of NETosis, thus protecting against excessive inflammation and disseminated intravascular coagulation (DIC) during sepsis.AbstractNeutrophil extracellular traps (NETs) evolved to protect the host against microbial infections and are formed by a web-like structure of DNA that is decorated with antimicrobial effectors. Due to their potent inflammatory functions, NETs also cause tissue damage and can favor and/or aggravate inflammatory diseases. This multipronged activity of NETs requires that the induction, release, and degradation of NETs are tightly regulated. Here we describe the key pathways that are intrinsic to neutrophils and regulate NETosis, and we review the most recent findings on how neutrophil extrinsic factors participate in the formation of NETs. In particular, we emphasize how bystander cells contribute to modifying the capacity of neutrophils to undergo NETosis. Finally, we discuss how these neutrophil extrinsic processes can be harnessed to protect the host against the excessive inflammation elicited by uncontrolled NET release.