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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.
Abstract
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.
