Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice

Kang, Xin; Hou, Along; Wang, Rui; Liu, Da; Xiang, Wei; Xie, Qiang-min; Zhang, Bo; Zheng, Wei; Miao, Hongming

doi:10.1042/cs20160192

Cited by 9 publications

(8 citation statements)

References 53 publications

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“…Low-dose also has reduced P65 motifs, a NF-κB subunit that is part of the canonical pathway involved in inflammation 103 . However, in monocytic cells that have already been stimulated with a Gram-negative bacteria, a second stimulation shows reduced P65 activity 104 , 105 . There is a possibility that sustained low-dosage of LPS may lead to such a reaction.…”

Section: Resultsmentioning

confidence: 99%

Epigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes

et al. 2022

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Emerging studies suggest that monocytes can be trained by bacterial endotoxin to adopt distinct memory states ranging from low-grade inflammation to immune exhaustion. While low-grade inflammation may contribute to the pathogenesis of chronic diseases, exhausted monocytes with pathogenic and immune-suppressive characteristics may underlie the pathogenesis of polymicrobial sepsis including COVID-19. However, detailed processes by which the dynamic adaption of monocytes occur remain poorly understood. Here we exposed murine bone-marrow derived monocytes to chronic lipopolysaccharide (LPS) stimulation at low-dose or high-dose, as well as a PBS control. The cells were profiled for genome-wide H3K27ac modification and gene expression. The gene expression of TRAM-deficient and IRAK-M-deficient monocytes with LPS exposure was also analyzed. We discover that low-grade inflammation preferentially utilizes the TRAM-dependent pathway of TLR4 signaling, and induces the expression of interferon response genes. In contrast, high dose LPS uniquely upregulates exhaustion signatures with metabolic and proliferative pathways. The extensive differences in the epigenomic landscape between low-dose and high-dose conditions suggest the importance of epigenetic regulations in driving differential responses. Our data provide potential targets for future mechanistic or therapeutic studies.

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Section: Resultsmentioning

confidence: 99%

Epigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes

et al. 2022

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“…Macrophages play important roles in the regulation of various immune responses and inflammatory processes [17,18]. In the context of organismal homeostasis, macrophages are critically involved in many age-related disorders including diabetes mellitus [19], atherosclerosis [20], Alzheimer's disease [21], and cancer [22].…”

Section: Introductionmentioning

confidence: 99%

Local cyclical compression modulates macrophage functionin situand alleviates immobilization-induced muscle atrophy

et al. 2018

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Physical inactivity gives rise to numerous diseases and organismal dysfunctions, particularly those related to aging. Musculoskeletal disorders including muscle atrophy, which can result from a sedentary lifestyle, aggravate locomotive malfunction and evoke a vicious circle leading to severe functional disruptions of vital organs such as the brain and cardiovascular system. Although the significance of physical activity is evident, molecular mechanisms behind its beneficial effects are poorly understood. Here, we show that massage-like mechanical interventions modulate immobilization-induced pro-inflammatory responses of macrophages and alleviate muscle atrophy. Local cyclical compression (LCC) on mouse calves, which generates intramuscular pressure waves with amplitude of 50 mmHg, partially restores the myofiber thickness and contracting forces of calf muscles that are decreased by hindlimb immobilization. LCC tempers the increase in the number of cells expressing pro-inflammatory proteins, tumor necrosis factor-α and monocyte chemoattractant protein-1 (MCP-1), including macrophages The reversing effect of LCC on immobilization-induced thinning of myofibers is almost completely nullified when macrophages recruited from circulating blood are depleted by administration of clodronate liposomes. Furthermore, application of pulsatile fluid shear stress, but not hydrostatic pressure, reduces the expression of MCP-1 in macrophages Together with the LCC-induced movement of intramuscular interstitial fluid detected by µCT analysis, these results suggest that mechanical modulation of macrophage function is involved in physical inactivity-induced muscle atrophy and inflammation. Our findings uncover the implication of mechanosensory function of macrophages in disuse muscle atrophy, thereby opening a new path to develop a novel therapeutic strategy utilizing mechanical interventions.

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“…Low-dose also has reduced p65 motifs, a NF-κB subunit that is part of the canonical pathway involved in inflammation 97 . However, in monocytic cells that have already been stimulated with a gram-negative bacteria, a second stimulation shows reduced p65 activity 98,99 . There is a possibility that sustained low-dosage of LPS may lead to such a reaction.…”

Section: Resultsmentioning

confidence: 99%

Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells

Hsieh

Geng

et al. 2021

Preprint

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Chronic, low-grade inflammation has a widespread and significant impact on health, especially in Western society. While inflammation is beneficial for the removal of microbes, low-grade inflammation never resolves and can cause or worsen other diseases. The process by which low-grade inflammation occurs remains poorly understood. Here we exposed murine bone-marrow derived monocytes to chronic lipopolysaccharide (LPS) stimulation at low dose or high dose, as well as a PBS control. The cells were profiled for genome-wide H3K27ac modification and gene expression. The gene expression of TRAM-deficient and IRAK-M-deficient monocytes with LPS exposure was also analyzed. We discover that low-grade inflammation preferentially utilizes the TRAM/TRIF-dependent pathway of TLR4 signaling, and induces the expression of interferon response genes. In contrast, acute inflammation uniquely upregulates metabolic and proliferative pathways that also appear to be TRAM-dependent. The extensive differences in the epigenomic landscape between low-dose and high-dose conditions suggest the importance of epigenetic regulations in driving differential responses. Our data provide potential targets for future mechanistic or therapeutic studies.

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Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice

Cited by 9 publications

References 53 publications

Epigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes

Epigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes

Local cyclical compression modulates macrophage functionin situand alleviates immobilization-induced muscle atrophy

Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells

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