Macrophage Extracellular Traps: A Scoping Review

Abstract

Tissue macrophages are derived from either circulating blood monocytes that originate in the bone marrow, or embryonic precursors that establish residence in tissues and are maintained independent of bone marrow progenitors. Macrophages perform diverse functions including tissue repair, the maintenance of homeostasis, and immune regulation. Recent studies have demonstrated that macrophages produce extracellular traps (ETs). ETs are an immune response by which a cell undergoes "ETosis" to release net-like material, with strands composed of cellular DNA that is studded with histones and cellular proteins. ETs are thought to immobilize and kill microorganisms, but also been implicated in disease pathology including aseptic inflammation and autoimmune disease. We conducted a scoping review to define what is known from the existing literature about the ETs produced by monocytes or macrophages. The results suggest that macrophage ETs (METs) are produced in response to various microorganisms and have similar features to neutrophil ETs (NETs), in that METs are produced by a unique cell death program (METosis), which results in release of fibers composed of DNA and studded with cellular proteins. METs function to immobilize and kill some microorganisms, but may also play a role in disease pathology.

Keywords: Extracellular traps; METosis; Macrophage.

Fig. 1

Search and review flowchart: 244 articles were identified by the primary PubMed search, 3 were excluded based on language, 241 underwent initial review of the abstracts, and 229 were excluded. Ultimately, 12 primary articles were identified for inclusion in this review based on the primary search; from the references of these articles, an additional 9 articles were identified. ETs, extracellular traps; NETs, neutrophil extracellular traps; METs, macrophage extracellular traps.

Fig. 2

Examples of METs. a Scanning electron micrograph image of a placental macrophage with expelled MET in response to S. agalactiae. Scale bar, 20 μm. As can be seen in the magnified panels (right), these fibers originate from the macrophage cell (bottom), and bacterial cells become embedded in these fibers (top). b Placental macrophage infected with S. agalactiae and treated with DNase I, leaving a defect in the macrophage cell surface where MET fibers exited the cell. Scale bar, 5 μm. c Confocal microscopy 3D reconstruction image of a placental macrophage MET in response to S. agalactiae. Scale bar, 10 μm. Cells were stained with Sytox green (green) for extracellular DNA and Hoechst 33342 (blue) for condensed chromatin. Extracellular DNA fibers (green) are seen extending beyond the nucleus structure (blue). Placental macrophages were obtained as published from deidentified, term, nonlabored placentae provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute [59]. All tissues were collected in accordance with Vanderbilt University Institutional Review Board approval (#131607). d, e PMA-differentiated THP-1 cells, an immortalized a monocyte cell line, produce METs (white arrows) in response to S. agalactiae, and these structures are absent when treated with DNase I (e). Cells were stained with Sytox green (green) and Hoechst 33342 (blue). Scale bars, 40 μm.