Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis

By A. Warnatsch, M. Ioannou, Qian Wang, V. Papayannopoulos. Science, 2015

1,103 citations recorded by the source corpus.

Neutrophil NETs drive atherosclerosis The buildup of fats, cholesterol, and other substances in arteries causes atherosclerosis, which restricts blood flow and can lead to heart attacks and stroke. Inflammation contributes to the pathogenesis of atherosclerosis, but exactly how is not fully understood. Warnatsch et al. now show that immune cells called neutrophils release NETs (neutrophil extracellular traps) (see the Perspective by Nahrendorf and Swirski). These NETs are composed of DNA and antimicrobial proteins, and in the setting of atherosclerosis they activate innate immune signaling pathways in macrophages. This causes the macrophages to secrete proinflammatory cytokines, exacerbating the disease. Indirectly, NETS also attract a specialized subset of T cells that further amplify the proinflammatory response. Science, this issue p. 316; see also p. 237 Neutrophils release networks of extracellular fibers that contribute to the pathogenesis of atherosclerosis. [Also see Perspective by Nahrendorf and Swirski] Secretion of the cytokine interleukin-1β (IL-1β) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1β, and then endogenous “danger” signals activate innate immune signaling complexes called inflammasomes to process IL-1β for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1β transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1β production. Cholesterol crystals triggered neutrophils to release neutrophil extracellular traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with neutrophils.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/2846ecd7a2eb14e2262e7cd53296170ba49b76e2

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In Immunology

1. C. Rosales
2. A. Grebe
3. M. Egeblad
4. E. Latz
5. P. Ridker
6. Florian Hoss
7. Peter Libby

Citations in the corpus

• NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, background): “CCs were shown to trigger the release of neutrophil extracellular traps (NETs), which in turn prime macrophages.(184) Moreover, atherosclerosis development and IL-1β plasma lev-”
• Pathophysiology of Atherosclerosis (2022, background): “Moreover, as phagocytic cells are unable to internalize large cholesterol crystals by scavenger receptors, their lysosomal content is directly secreted to the interstitial space, promoting a more intense immune response [207,208].”
• From CRP to IL-6 to IL-1: Moving Upstream To Identify Novel Targets for Atheroprotection (2016, background): “traps which prime macrophages to produce the precursor proIL-1β.(87) Neutrophil extracellular traps comprise extracellular released DNA fibers that form net-like entities which bind bac-”
• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “NETs can also regulate cytokine production from macrophages in atherosclerosis (Warnatsch et al., 2015), and induce endothelial dysfunction directly by activation and damage of endothelial cells (Knight et al., 2014).”
• Neutrophil extracellular traps in COVID-19. (2020, background): “NETs are drivers of cardiovascular disease by propagating inflammation in vessel walls 17 .”