Mechanisms and immune crosstalk of neutrophil extracellular traps in response to infection

Abstract

Neutrophil extrusion of neutrophil extracellular traps (NETs) in a process called NETosis provides immune defense against extracellular bacteria. It has been observed that bacteria are capable of activating neutrophils to release NETs that subsequently kill them or at least prevent their local spread within host tissue. However, existing studies have mainly focused on the isolated function of NETs, with less attention given to their anti-bacterial mechanisms through interactions with other immune cell populations. The net effect of these complex intercellular interactions, which may act additively, synergistically, or antagonistically, is a critical determinant in the outcomes of host-pathogen interactions. This review summarizes the mechanisms underlying classic NET formation and their crosstalk with the immune system, offering novel insights aimed at balancing the anti-microbial function with their potential inflammatory risks.

Keywords: adaptive immunity; bacterial infection; evasion; innate immunity; neutrophil; neutrophil extracellular traps (NETs).

Fig 1

NET formation mechanisms. NET formation can be primarily categorized into two types. The first type is (a) suicidal NETosis, which is initiated by PMA, bacteria, and various cytokines. These extracellular signaling events activate the NADPH oxidase complex (NOX) and subsequently lead to reactive oxygen species (ROS) burst, promoting granule cleavage. The activation of PAD4 and the translocation of MPO and NE into the nucleus contribute to the citrullination of histones and chromatin decondensation. Ultimately, NETs are released and cause neutrophil death. An alternative mechanism, termed (b) vital NETosis, occurs in a NOX-independent manner. Upon interaction with Staphylococcus aureus or lipopolysaccharide (LPS)-activated platelets, receptors trigger the influx of calcium ions through the small conductance potassium channel member three (SK3) channel, which activates PAD4. Afterward, the decondensed chromatin coated with anti-microbial proteins is expelled via vesicles without plasma membrane disruption. Additionally, following pretreatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and subsequent stimulation with LPS or C5a, the mitochondria of neutrophils also exhibit NET formation while retaining neutrophils’ normal physiological functions. Abbreviations: ER, endoplasmic reticulum; MPO, myeloperoxidase; NE, neutrophil elastase; PMA, phorbol 12-myristate 13-acetate; PAD4, peptidylarginine deiminase 4.

Fig 2

NETs regulate the immune microenvironment. NETs interact with innate and adaptive immunity during infection. (a) NET-derived substances activate cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the cytosol of macrophages, triggering a series of proinflammatory cytokine releases. Meanwhile, the crosstalk between NETs and macrophages achieves optimal bactericidal activity through the internalization of NETs. Additionally, macrophages exposed to bacterial environments for extended periods can also form METosis structures. (b) NETs impair natural killer cell function via carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Plasmacytoid dendritic cells are activated by DNA complexes in NETs from infected neutrophils, triggering type I interferon (IFN) (α and β) production while acting as a conduit between innate and adaptive immunity to activate T lymphocytes. (c) NETs can directly lower the activation threshold of T-cell responses and initiate the response of protective Th1 and T-helper 17 (Th17) cells. (d) NETs support B-cell activation via the B-cell activating factor (BAFF), and B-cell-derived immune complexes further activate neutrophils by binding to FC-γ receptor IIIb (FC-γ RIIIb), thereby inducing additional NET formation.