NETosis in Wound Healing: When Enough Is Enough

Abstract

The neutrophils extracellular traps (NETs) are a meshwork of chromatin, histonic and non-histonic proteins, and microbicidal agents spread outside the cell by a series of nuclear and cytoplasmic events, collectively called NETosis. NETosis, initially only considered a defensive/apoptotic mechanism, is now considered an extreme defensive solution, which in particular situations induces strong negative effects on tissue physiology, causing or exacerbating pathologies as recently shown in NETs-mediated organ damage in COVID-19 patients. The positive effects of NETs on wound healing have been linked to their antimicrobial activity, while the negative effects appear to be more common in a plethora of pathological conditions (such as diabetes) and linked to a NETosis upregulation. Recent evidence suggests there are other positive physiological NETs effects on wound healing that are worthy of a broader research effort.

Keywords: inflammation; innate immunity; netosis; wound healing.

Figure 1

Molecular mechanism involved in the neutrophils extracellular traps (NETs) formation process. Following pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), molecules binding to toll-like receptors (TLR) in a neutrophil granulocyte several steps characterizing the evolution, formation, and extrusion of NETs. (A) Cytoplasmatic events: cytoplasm granules are shifted into the nucleus for decondensing DNA, the nucleus loses its integrity, and NETs meshwork is released in the extracellular space by gasdermin D pores. After NETs extrusion, the granulocyte preserves its phagocytic ability for some hours. (B) Nuclear events: nuclear DNA-histones is was decondensed by azurophilic granulocyte enzymes, then linker H1 histone is cleaved off and histone 3 and 4 are citrullinated, inducing DNA decondensation.

Figure 2

NETosis in physiologic (A) and pathologic conditions or ageing (B). Interleukins (ILs), tumor necrosis factors (TNFs), and interferones (IFNs). (A) NETs extrusion is adequate to the defensive anti-microbial action, and NETs are then removed by macrophages; inflammatory factors drop down. (B) Basal or induced NETs extrusion is enhanced, and they are not efficiently removed by macrophages; inflammatory factors increase, leading to long-lasting inflammation.

Figure 3

NETs in wound healing: the physiological release of NETs and macrophage clearance (A) actions are essential to support the physiological response of fibroblasts and keratinocytes to heal wounds (B). Excessive NETs extrusion and inefficient macrophage clearance (C) increases in situ inflammation and altered both fibroblast and keratinocyte pro-healing action (D).