Abstract
Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis.
Highlights
Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood
As determined by Oil Red O staining of the aorta sections, chronic injection of superlow-dose LPS significantly elevated the lipid deposition ratio within the atherosclerotic plaques in ApoE-deficient mice fed with the western high-fat diet (HFD) for 8 weeks, as compared with mice fed with HFD alone (Fig. 1a,b)
Based on immuno-histochemical staining, we found that HFD-fed ApoE-deficient mice conditioned with super-low-dose LPS had significantly lower levels interleukin-1 receptor associated kinase M (IRAK-M) within the plaque macrophages (Supplementary Fig. 5)
Summary
Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. Under non-resolving inflammatory conditions, it has been suggested that monocytes may fail to develop endotoxin tolerance and adopt a sustained inflammatory state conducive for the pathogenesis of atherosclerosis[5]. Studies conducted in vitro suggest that subclinical super-low levels of endotoxin fail to cause compensatory endotoxin tolerance and may instead be capable of inducing low-grade inflammatory responses from cultured monocytes/macrophages[10,11]. We reported that the reduction of homeostatic negative regulators necessary for causing tolerance and preventing runaway inflammation may be a potential cause for low-grade inflammatory polarization of macrophages in vitro[11,12]. We reported that monocytes challenged with subclinical super-low-dose LPS in vitro have reduced levels of IRAK-M, with unknown mechanism[11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
