Modulation of neutrophil NETosis: interplay between infectious agents and underlying host physiology

Abstract

The ability of neutrophils and other leucocyte members of the innate immune system to expel their DNA into the extracellular environment in a controlled manner in order to trap and kill pathogenic microorganisms lead to a paradigm shift in our understanding of host microbe interactions. Surprisingly, the neutrophil extracellular trap (NET) cast by neutrophils is very wide and extends to the entrapment of viruses as well as multicellular eukaryotic parasites. Not unexpectedly, it has emerged that pathogenic microorganisms can employ a wide array of strategies to avoid ensnarement, including expression of DNAse enzymes that destroy the lattice backbone of NETs. Alternatively, they may use molecular mimicry to avoid detection or trigger events leading to the expression of immune modulatory cytokines such as IL-10, which dampen the NETotic response of neutrophils. In addition, the host microenvironment may contribute to the innate immune response by the production of lectin-like molecules that bind to bacteria and promote their entrapment on NETs. An example of this is the production of surfactant protein D by the lung epithelium. In addition, pregnancy provides a different challenge, as the mother needs to mount an effective response against pathogens, without harming her unborn child. An examination of these decoy and host response mechanisms may open the path for new therapies to treat pathologies mediated by overt NETosis.

Fig. 1

Mechanisms of defense against bacteria and fungi and strategies of evasion of NET entrapment. NETs can be induced by both Gram-positive or Gram-negative bacteria (a). Evasion of the antimicrobial activity of NETs may include the use of nucleases that attack the DNA backbone of the NETs' lattice structure (a) or elements of molecular mimicry that stimulate the production of the potent immune-modulating cytokines (b). NE neutrophil elastase, PMN polymorphonuclear neutrophil, MPO myeloperoxidase, LL37 cathelicidin, CG cathepsin G, IL10 interleukin 10, TGFβ transforming growth factor beta

Fig. 2

Neutrophils and macrophages cooperate in order to confront mycobacterial infections. Mycobacterium bacilli induce leucocyte clustering or aggregation and, subsequently, NETosis, but not killing of these pathogens. Macrophages are able to ingest neutrophil azurophil granular proteins and dispatch invasive mycobacteria. The generation of ETs (extracellular traps) by macrophages is dependent on the presence of IFN-γ and the mycobacterial ESX-1 system, which mediate phagosomal rupture and subsequent bacterial escape

Fig. 3

Immunothrombosis supports the innate immune defense against pathogens. Immunothrombosis involves an intricate interplay between complement, coagulation, and innate immune effector cells. By assembly of a thrombus around the pathogenic microorganisms, their systemic spread is prevented and the damage to the host is minimized. PRR pattern recognition receptor, TLR toll-like receptor, TF tissue factor, vWF von Willebrand factor, NE neutrophil elastase, PMN polymorphonuclear neutrophil. Adapted and modified from Engelmann et al. [59]

Fig. 4

HIV downmodulates NETosis via dendritic cells. HIV triggers NETosis via a process that involves TLR7 and TLR8, trapping individual HIV virions in the NET lattice. Viral binding to CD209 anchors the virions on dendritic cells (DC), thereby promoting the efficient infection of CD4⁺ T cells. The gp120/CD209-primed DC cells produce the immune-modulating cytokine IL-10, leading to a reduction in NETotic capability, thereby preventing PMN from effectively engaging and eliminating HIV

Fig. 5

NETosis—modulation by the respiratory system. The response of the respiratory system to infection is complex involving chemokine recruitment of neutrophils and monocytes into the lumen of the alveoli. The NETotic release of cytotoxic DNA–protein complexes with NE, MPO, LL37, and other neutrophil proteases increases mucus viscosity and contributes to lung epithelial damage, thereby perpetuating a vicious cycle of injury and inflammation. Innate immune surfactant proteins (also termed collectins) contribute in maintaining the lungs' homeostasis with minimal inflammation. NETs are removed by DNAse degradation and macrophage ingestion. A delicate equilibrium between NETosis and NET clearance is fundamental for the successful combating of infectious agents with minimum tissue damage. NE neutrophil elastase, MPO myeloperoxidase, LL37 cathelicidin, SP-A surfactant protein A, SP-D surfactant protein D, PMN polymorphonuclear neutrophil, Mφ macrophages. Adapted and modified from Chen et al. [81]