Going Fishing

With the discovery of neutrophil extracellular traps (NETs) by Volker Brinkmann and his colleagues in 2004 [1], a new chapter in the book of innate immunity was opened. It is more than obvious that this chapter has not yet been closed since many researchers are still contributing to it. It was first believed that NETs play an important role in immobilizing bacterial pathogens, but evidence is now accumulating that they are also involved in many other processes, such as the induction of inflammatory reactions [2, 3]. Moreover, NETs can promote immunothrombotic processes since they activate the coagulation system [4]. This said, there is also a growing number of publications reporting that overwhelming NET formation can contribute to a plethora of pathological processes [5, 6]. A discussion has therefore arisen as to whether NETs can act as a double-edged sword. This is exemplified by a number of articles with titles such as “Neutrophil Extracellular Traps as a New Paradigm in Innate Immunity: Friend or Foe?” [7] or “Neutrophil Extracellular Traps - The Dark Side of Neutrophils” [8].

As is the case for many other inflammatory host responses, the amplitude of NET induction will determine whether their formation is part of an adequate immune reaction or a pathophysiological mechanism used by invading bacteria to cause systemic complications. In patients with severe infectious diseases, systemic inflammatory responses, such as a cytokine storm, are part of the clinical picture [9, 10]. These life-threatening conditions are often a consequence of a pathological activation of pattern recognition receptors (PRRs) by microbial pathogens [11]. However, the question remains of how the host can distinguish between commensal and pathogenic bacteria, since both utilize similar ligands for the activation of PRRs. One concept addressing this question was published in 2002 by Polly Matzinger [12] who postulated that a danger signal is needed to discriminate between self and non-self. Though her model concerns the adaptive immune system and the prevention of autoimmune reactions, the danger model can also be applied to innate immune mechanisms, as described by Philippe Sansonetti [13] in 2016.

Today, we know that during infection the host can mobilize so-called damage-associated pattern molecules (DAMPs), also known as alarmins, triggering innate immune responses [14]. One of the best-characterized proteins within this family of inflammatory mediators is high mobility group box-1 (HMGB1) [15], but also extracellular histones and antimicrobial peptides (AMPs) have lately attracted significant attention [16]. Thus, it seems plausible that DAMPs provide the danger signals that the innate immune system needs to distinguish whether a PRR is activated by a commensal or pathogenic microorganism. Also, here it seems that an overwhelming release of DAMPs cause more harm than benefit, since the inflammatory DAMP response can reach pathological levels under certain conditions. For instance, extracellular histones, when released at a high concentration, can cause death within minutes, as shown in a murine sepsis model by Xu et al. [17]. The host should therefore have developed counter mechanisms that help to decrease DAMP signaling processes and prevent the induction of pathological inflammatory reactions. So far, the regulation of DAMPs has not been intensively studied. However, there have been some interesting hints reported in the literature. Many DAMPs, including HMGB1 and extracellular histones as well as AMPs, have an overall positive net charge. Cells like endothelial and epithelial cells express proteins such as p33 and osteopontin, respectively, which are highly negatively charged [18, 19]. Both proteins have in common that their binding to DAMPs, including extracellular histones and AMPs, abolish their inflammatory activities [20, 21]. Thus, it is tempting to speculate that proteins like p33 and osteopontin are endogenous regulators of DAMP signaling. However, more work is needed to support this hypothesis.

In this issue of Journal of Innate Immunity, Ariane Neumann and her coworkers [22] show that, in addition to downregulating inflammatory host reactions, p33 is also able to annul histone- and LL-37-induced NET formation. To this end, neutrophils take up extracellular p33, which can be released for instance from necrotic endothelial cells. Once internalized, p33 blocks the activity of myeloperoxidase, which is otherwise required for the release of the nucleic material. These findings are in line with the concept that the host can produce its own regulators that dampen an otherwise overwhelming and deleterious immune response. This is a very interesting and still unexplored area of research. We therefore believe that future work will show whether regulation of DAMP signaling can be used as a treatment to prevent the induction of overwhelming and uncontrolled host responses to severe and life-threatening infections.

Arne Egesten, Lund

Heiko Herwald, Lund