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.
Highlights
Secretion of the cytokine interleukin-1β (IL-1β) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps
To examine how neutrophils respond during atherosclerosis we investigated the effect of cholesterol crystals on human blood-derived neutrophils
NETosis depended on reactive oxygen species (ROS) as it was blocked by the NADPH oxidase inhibitor diphenylene iodonium (DPI) or an inhibitor (NEi) of the neutrophil-specific proteases neutrophil elastase (NE) and proteinase 3 (PR3) [17] but not by Cl-amidine which inhibits peptidylarginine deiminase (PAD) enzymes implicated in NETosis [18] (Fig. 1A, B and S1E)
Summary
Secretion of the cytokine interleukin-1β (IL-1β) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps. When placed on HFD, ApoE and ApoE/NE/PR3 deficient mice exhibited similar weight gain (Fig. S3A) and blood cholesterol, triglyceride and LDL concentrations (Fig. S3B). DNase injections to ApoE deficient mice on HFD for 6 weeks resulted in a comparable 3-fold reduction in lesion size, excluding that the proteases played NET-independent roles (Fig. 2B and C).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
