The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis.
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.
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Shuo
S
Geng
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Keqiang
K
Chen
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Ruoxi
http://orcid.org/0000-0002-8719-341X
R
Yuan
Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Liang
L
Peng
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Urmila
U
Maitra
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Na
N
Diao
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Chun
C
Chen
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Yao
Y
Zhang
Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Yuan
Y
Hu
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chen-Feng
CF
Qi
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Susan
S
Pierce
School of Public Health, National Sun Yat-Sen University, Guangzhou 510080, China.
Wenhua
W
Ling
Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Huabao
H
Xiong
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Liwu
http://orcid.org/0000-0001-8870-5299
L
Li
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D016764:Cell Polarity; D018450:Disease Progression; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology*; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000378:metabolism; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism
D008070:Lipopolysaccharides; D035683:MicroRNAs; C529080:Mirn24 microRNA, mouse; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D051901:Smad4 Protein; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse