Oxidative Burst-Dependent NETosis Is Implicated in the Resolution of Necrosis-Associated Sterile Inflammation

Abstract

Necrosis is associated with a profound inflammatory response. The regulation of necrosis-associated inflammation, particularly the mechanisms responsible for resolution of inflammation is incompletely characterized. Nanoparticles are known to induce plasma membrane damage and necrosis followed by sterile inflammation. We observed that injection of metabolically inert nanodiamonds resulted in paw edema in WT and Ncf1** mice. However, while inflammation quickly resolved in WT mice, it persisted over several weeks in Ncf1** mice indicating failure of resolution of inflammation. Mechanistically, NOX2-dependent reactive oxygen species (ROS) production and formation of neutrophil extracellular traps were essential for the resolution of necrosis-induced inflammation: hence, by evaluating the fate of the particles at the site of inflammation, we observed that Ncf1** mice deficient in NADPH-dependent ROS failed to generate granulation tissue therefore being unable to trap the nanodiamonds. These data suggest that NOX2-dependent NETosis is crucial for preventing the chronification of the inflammatory response to tissue necrosis by forming NETosis-dependent barriers between the necrotic and healthy surrounding tissue.

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface

“…Later, the accumulation and aggregation of NETs actively prevent the dissemination of the inflammatory stimuli because they degrade inflammatory mediators. Chronic inflammatory responses to necrotic tissue are prevented by NETs that form barriers between the necrotic areas and the healthy surrounding tissues . Neutrophil‐driven inflammations are often terminated by proteolysis of cytokines and chemokines by NET‐born serine proteases limiting the inflammatory focus .…”

Missing in action—The meaning of cell death in tissue damage and inflammation

“…The migration of neutrophils toward dying cells is inhibited by secretion of lactoferrin, which acts like a “keep out” signal . In case of an enhanced collateral activation of neutrophils, lactoferrin would also contribute to dampening of inflammation by enhancing the aggregation of NETs (neutrophil extracellular traps) …”

“…Consequences of NET formation in sterile diseases. Neutrophil extracellular traps ( NET s) form in response to various stimuli (eg, microparticles or crystals, disturbed ionic milieu or necrotic tissue). The aim of neutrophils in sterile diseases is containment of danger and injury.…”

“…A further example of the walling off areas of sterile necrotic by NETs was characterized by employing nanodiamonds below the critical size of 50 nm. Injection of these particles in tissues causes local sterile necrosis accompanied by a neutrophil‐driven initial inflammatory reaction that is promptly controlled by the subsequent formation of aggNETs . The aggressive nanodiamonds get sequestered and immobilized by the physical action of the aggNETs and the spreading of the inflammatory reaction gets dampened by the inactivation of chemokines by aggNETs.…”

“…12 In case of an enhanced collateral activation of neutrophils, lactoferrin would also contribute to dampening of inflammation by enhancing the aggregation of NETs (neutrophil extracellular traps). 13,14…”