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The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis.

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.

SUBMITTER: Geng S

PROVIDER: S-EPMC5105176 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis.

Geng Shuo S Chen Keqiang K Yuan Ruoxi R Peng Liang L Maitra Urmila U Diao Na N Chen Chun C Zhang Yao Y Hu Yuan Y Qi Chen-Feng CF Pierce Susan S Ling Wenhua W Xiong Huabao H Li Liwu L

Nature communications 20161108

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 ...[more]

PMID: 27824038

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Project description:Hyperhomocysteinemia (HHcy) has been shown to promote vascular inflammation and atherosclerosis, but the underlying mechanisms remain largely unknown. The NLRP3 inflammasome has been identified as the cellular machinery responsible for activation of inflammatory processes. In this study, we hypothesized that the activation of NLRP3 inflammasomes contributes to HHcy-induced inflammation and atherosclerosis. ApoE-/- mice were fed regular chow, high-fat (HF) diet, or HF plus high methionine diet to induce HHcy. To assess the role of NLRP3 inflammasomes in HHcy-aggravated atherosclerosis, NLRP3 shRNA viral suspension was injected via tail vein to knock down the NLRP3 gene. Increased plasma levels of IL-1β and IL-18, aggravated macrophage infiltration into atherosclerotic lesions, and accelerated development of atherosclerosis were detected in HHcy mice as compared with control mice, and were associated with the activation of NLRP3 inflammasomes. Silencing the NLRP3 gene significantly suppressed NLRP3 inflammasome activation, reduced plasma levels of proinflammatory cytokines, attenuated macrophage infiltration and improved HHcy-induced atherosclerosis. We also examined the effect of homocysteine (Hcy) on NLRP3 inflammasome activation in THP-1-differentiated macrophages in the presence or absence of NLRP3 siRNA or the caspase-1 inhibitor Z-WEHD-FMK. We found that Hcy activated NLRP3 inflammasomes and promoted subsequent production of IL-1β and IL-18 in macrophages, which were blocked by NLRP3 gene silencing or Z-WEHD-FMK. As reactive oxygen species (ROS) may have a central role in NLRP3 inflammasome activation, we next investigated whether antioxidant N-acetyl-l-cysteine (NAC) prevented Hcy-induced NLRP3 inflammasome activation in macrophages. We found Hcy-induced NLRP3 inflammasome activation was abolished by NAC. Treatment with NAC in HHcy mice also suppressed NLRP3 inflammasome activation and improved HHcy-induced atherosclerosis. These data suggest that the activation of NLRP3 inflammasomes contributes to HHcy-aggravated inflammation and atherosclerosis in apoE-/- mice. Hcy activates NLRP3 inflammasomes in ROS-dependent pathway in macrophages. These results may have implication for the treatment of HHcy-associated cardiovascular diseases.

Project description:IntroductionIn patients with ulcerative colitis (UC), dysplasia develops in 10%-20% of cases. The persistence of low-grade dysplasia (LGD) in UC in 2 consecutive observations is still an indication for restorative proctocolectomy. Our hypothesis is that in the case of weak cytotoxic activation, dysplasia persists. We aimed to identify possible immunological markers of LGD presence and persistence.MethodsWe prospectively enrolled 112 UC patients who underwent screening colonoscopy (T0) who had biopsies taken from their sigmoid colon. Ninety of them had at least a second colonoscopy (T1) with biopsies taken in the sigmoid colon and 8 patients had dysplasia in both examinations suggesting a persistence of LGD in their colon. Immunohistochemistry and real time polymerase chain reaction for CD4, CD69, CD107, and CD8β messenger RNA (mRNA) expression and flow cytometry for epithelial cells expressing CD80 or HLA avidin-biotin complex were performed. Non-parametric statistics, receiver operating characteristic curves analysis, and logistic multiple regression analysis were used.ResultsThirteen patients had LGD diagnosed at T0. The mucosal mRNA expression of CD4, CD69, and CD8β was significantly lower than in patients without dysplasia (P = 0.033, P = 0.046 and P = 0.007, respectively). A second colonoscopy was performed in 90 patients after a median follow-up of 17 (12-25) months and 14 of the patients were diagnosed with LGD. In these patients, CD8β mRNA expression at T0 was significantly lower in patients without dysplasia (P = 0.004). A multivariate survival analysis in a model including CD8β mRNA levels and age >50 demonstrated that both items were independent predictors of dysplasia at follow-up (hazard ratio [HR] = 0.47 [95% confidence interval [CI]: 0.26-0.86], P = 0.014, and HR = 13.32 [95% CI: 1.72-102.92], P = 0.013).DiscussionThese data suggest a low cytotoxic T cell activation in the colonic mucosa of UC patients who do not manage to clear dysplasia. Thus, low level of CD8β mRNA expression in non-dysplastic colonic mucosa might be considered in future studies about the decision making of management of LGD in UC.

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The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis.

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The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis.

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