Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet–Fed Mice

Guo, Honghui; Diao, Na; Yuan, Ruoxi; Chen, Keqiang; Geng, Shuo; Li, Mingsong; Li, Liwu

doi:10.4049/jimmunol.1500130

Cited by 35 publications

(37 citation statements)

References 47 publications

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“…As systemic LPS injection may not only affect monocyte programming, but also other tissues such as the liver and metabolic processes2930, we further examined whether the re-programmed monocytes, instead of other systemic effects of LPS, may be causally involved in the exacerbation of atherosclerosis. To address this issue, we performed adoptive transfer experiment with in vitro programmed monocytes.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…100 ng/ml (Fig. 1E), indicating that it contributes primarily to repression of macrophage responses rather than training (25,26). Time-course stimulation showed that IRAK-M mRNA was induced after 6 h, peaking at 12 and 24 h following treatment with 100 ng/ml of LPS (Fig.…”

Section: Resultsmentioning

confidence: 92%

Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages

Lyroni

Patsalos

Daskalaki

et al. 2017

The Journal of Immunology

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During macrophage activation, expression of IL-1R-associated kinase (IRAK)-M is induced to suppress TLR-mediated responses and is a hallmark of endotoxin tolerance. Endotoxin tolerance requires tight regulation of genes occurring at the transcriptional and epigenetic levels. To identify novel regulators of IRAK-M, we used RAW 264.7 macrophages and performed a targeted RNA interference screen of genes encoding chromatin-modifying enzymes, signaling molecules, and transcription factors involved in macrophage activation. Among these, the transcription factor CCAAT/enhancer binding protein (C/EBP)β, known to be involved in macrophage inactivation, was necessary for the induction of IRAK-M expression. Chromatin immunoprecipitation showed that C/EBPβ was recruited to the IRAK-M promoter following LPS stimulation and was indispensable for IRAK-M transcriptional activation. Among histone 3-modifying enzymes, our screen showed that knockdown of the histone 3 lysine 27 (H3K27) methyltransferase and part of the polycomb recessive complex 2, enhancer of Zeste 2, resulted in IRAK-M overexpression. In contrast, knockdown of the H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat X chromosome suppressed the induction of IRAK-M in response to LPS stimulation. Accordingly, we demonstrated that H3K27 on the IRAK-M promoter is trimethylated in unstimulated cells and that this silencing epigenetic mark is removed upon LPS stimulation. Our data propose a mechanism for IRAK-M transcriptional regulation according to which, in the naive state, polycomb recessive complex 2 repressed the IRAK-M promoter, allowing low levels of expression; following LPS stimulation, the IRAK-M promoter is derepressed, and transcription is induced to allow its expression.

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“…Yet, we cannot rule out the involvement of others toxic compounds, particularly during NAFPD progression. Indeed, some studies suggest a possible causal relationship between NAFLD/ NAFPD-related disorders with chronic intermittent hypoxia elicited by obstructive sleep apnea [165,166], bacterial endotoxin [167][168][169], glyceraldehyde [170], methylglyoxal [171][172][173], advanced glycation end products (AGE)s [174], receptor for advanced glycation end products (RAGE) [175], nitric oxide/peroxynitrite [176], and lipid peroxidation end products [177,178].…”

Section: Discussionmentioning

confidence: 99%

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

Medeiros¹,

Lima²

2016

Gastroenterol Hepatol Endosc

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Nonalcoholic fatty pancreas disease (NAFPD) is closely linked to nonalcoholic steatohepatitis (NASH), suggesting that the two conditions share a common etiopathogenetic background. In Addition, growing evidence indicates that endogenous ethanol (EE) plays a fundamental role in NASH pathogenesis. Accordingly, it is intuitively appealing to assume that EE plays also a causative role in NAFPD development. This connection is further supported by the finding that NAFPD shares with alcoholic fatty pancreas disease (AFPD) similar metabolic signaling pathways and histopathological features. However, low blood alcohol concentrations (BAC) along with the alleged inability of gut microbiota to produce toxic amounts of ethanol are the main obstacles to validate the idea of an endogenous alcoholic fatty pancreas disease (EAFPD). Here, we provide a mechanistic explanation reconciling the EAFPD hypothesis with these apparently conflicting observations. The key conclusions of our investigation are as follows. First, ethanol is a prodrug, implicating that under extensive presystemic metabolism BACs can be low and/ or absent. Second, oro-gastrointestinal microbiota may produce higher amounts of ethanol than those required to cause AFPD. Last, livers of NASH/NAFPD individuals overexpress all genes encoding alcohol-metabolizing enzymes identically to livers of patients with alcoholic hepatitis. Even more importantly, the upregulation of these genes is higher in the early steatotic stage of nonalcoholic fatty liver disease than in alcoholic hepatitis. This suggests a greater exposure of the liver, and by extension, of the pancreas, to ethanol in the former than in the latter condition. In summary, this paper provides a mechanistic framework for how NAFPD indeed may be an EAFPD.

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Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet–Fed Mice

Cited by 35 publications

References 47 publications

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

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

Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

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