Abstract 20934: Chronic Polarization of Inflammatory Monocytes by Super-Low Grade Endotoxin Aggravates the Pathogenesis of Atherosclerosis

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The subclinical levels of Gram negative bacterial endotoxin, LPS, circulating in the blood are prevalent in the individuals with adverse health conditions or lifestyles. LPS is a potent agent in the dynamic programming of monocytes, and altered innate immune homeostasis mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis. However, the mechanisms responsible for the sustainment of inflammatory monocytes during atherosclerosis are poorly understood. We hypothesized that the selective modulation of molecular switches in monocytes by super-low dose LPS may facilitate the establishment of non-resolving inflammation during atherosclerosis. We challenged high-fat-diet (HFD) fed ApoE deficient mice with chronic LPS administration, and observed that LPS effectively induced expansion of Ly6Chigh pro-inflammatory monocytes with elevated levels of CCR5, MCP-1, and reduced SR-B1. Compare to PBS administration, chronic injection of super-low dose LPS significantly elevated the lipid deposition within the atherosclerotic plaques in HFD fed ApoE deficient mice, while induced remarkable reduction in collagen content of the plaques. To test whether the LPS reprogrammed monocytes, instead of systemic effects of LPS, may contribute the exacerbation of atherosclerosis, we performed adoptive transfer experiment. Bone-marrow monocytes harvested from ApoE deficient mice were primed in vitro with super-low dose LPS for 5 days, and then intravenously injected into HFD fed ApoE once weekly for 1 month. We observed significant increases of the plaque sizes as well as lipid deposition in atherosclerotic lesions, indicating that programmed monocytes directly aggravated atherosclerosis progression. At the molecular level, we observed that monocytes programmed by super-low dose LPS maintained higher levels of transcription factor IRF5 and reduced levels of a critical inflammatory repressor, Blimp-1. Intriguingly, the inflammatory monocyte priming by super-low dose LPS was dependent upon TRAM/TRIF but not MyD88. In conclusion, our data suggest super-low grade LPS may program sustained low-grade inflammatory monocytes that are conducive for the chronic pathogenesis of atherosclerosis.

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