Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization

Lu, Geming; Zhang, Ruihua; Geng, Shuo; Peng, Liang; Jayaraman, Padmini; Chen, Chun; Xu, Feifong; Yang, Jianjun; Qin, Li; Zheng, Hao; Shen, Kimberly; Wang, Juan; Liu, Xiyu; Wang, Weidong; Zheng, Zihan; Chen, Qi; Si, Chuanping; He, John Cijiang; Liu, Kebin; Lira, Sérgio A.; Sikora, Andrew G.; Li, Liwu; Xiong, Huabao

doi:10.1038/ncomms7676

Cited by 158 publications

(122 citation statements)

References 56 publications

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“…This was somewhat unexpected and could be explained by the fact that we found an increase of both C/EBPβ (M2 transcriptional regulator) and HIf1α (M1 transcriptional regulator) after polarization with LPS or INFγ in isolated KCs from miR-155 KO mice. A recent study revealed that iNOS deficient mice had enhanced M1 macrophage differentiation after polarization but without having major effects on M2 macrophages [35]. Our results support the notion that macrophages likely exist as a mixed population of M1/M2 in vivo or as hybrid phenotypes instead of an entirely polarized M1 or M2 phenotype [35].…”

Section: Discussionsupporting

confidence: 87%

“…A recent study revealed that iNOS deficient mice had enhanced M1 macrophage differentiation after polarization but without having major effects on M2 macrophages [35]. Our results support the notion that macrophages likely exist as a mixed population of M1/M2 in vivo or as hybrid phenotypes instead of an entirely polarized M1 or M2 phenotype [35]. …”

Section: Discussionsupporting

confidence: 87%

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The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Bala

Csák

Saha

et al. 2016

Journal of Hepatology

234

245

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Background & Aims Alcoholic liver disease (ALD) ranges from fatty liver to inflammation and cirrhosis. miRNA-155 is an important regulator of inflammation. In this study, we describe the in vivo role of miR-155 in ALD. Methods Wild type, WT (C57/BL6J) or miR-155 KO and TLR4 KO mice received Lieber-DeCarli diet for 5 weeks. Some mice received corn oil or CCl4 for 2 or 9 weeks. Results We found that miR-155 KO mice are protected from alcohol-induced steatosis and inflammation. The reduction in alcohol-induced fat accumulation in miR-155 KO mice was associated with increased PPRE and PPARα (miR-155 target) binding and decreased MCP1 production. Treatment with a miR-155 inhibitor increased PPARγ expression in naive and alcohol treated RAW macrophages. Alcohol increased lipid metabolism genes (FABP4, LXRα, ACC1 and LDLR) in WT mice and this was prevented in KO mice. Alcohol diet induced increase in the number of CD163+CD206+ infiltrating macrophages and neutrophils in WT was prevented in miR-155 KO mice. Kupffer cells isolated from miR-155 KO mice exhibited predominance of M2 phenotype when exposed to M1 polarized signals and this was due to increased C/EBPβ. Profibrotic genes were attenuated in miR-155 KO mice after alcohol diet or CCl4 treatment. Compared to WT attenuation in CCl4 induced hydroxyproline and α SMA was observed in KO mice. Finally, we show TLR4 signaling regulates miR-155 as TLR4 KO mice showed no induction of miR-155 after alcohol diet. Conclusions Collectively our results demonstrated the role of miR-155 in alcohol-induced steatohepatitis and fibrosis in vivo.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Bala

Csák

Saha

et al. 2016

Journal of Hepatology

234

245

View full text Add to dashboard Cite

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“…We intend to build a simple and abstract mathematical model to illustrate the role of IRAK-M in preventing leaky low-grade inflammation, based on experimental evidence from this study as well as previous studies6566. We posit that sustained and low levels of JNK activities potentiate MCP-1 expression and non-resolving low-degree inflammation.…”

Section: Methodsmentioning

confidence: 93%

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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“…Recent studies from our group and other suggest another intriguing aspect of innate immunity programming and memory, in that innate leukocytes may not only be able to recognize different combinations of extra-cellular stimulants, but also discern their relative signal strength (Baker et al, 2014;Deng et al, 2013;Lu et al, 2015;Maitra et al, 2012;Maitra et al, 2011;Morris et al, 2014). This is reflected in the cardinal example of endotoxin priming and tolerance.…”

Section: Signal Strength-dependent Programming Of Innate Leukocytesmentioning

confidence: 89%

Dynamic modulation of innate immunity programming and memory

Yuan

2016

Sci. China Life Sci.

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Recent progress harkens back to the old theme of immune memory, except this time in the area of innate immunity, to which traditional paradigm only prescribes a rudimentary first-line defense function with no memory. However, both in vitro and in vivo studies reveal that innate leukocytes may adopt distinct activation states such as priming, tolerance, and exhaustion, depending upon the history of prior challenges. The dynamic programming and potential memory of innate leukocytes may have far-reaching consequences in health and disease. This review aims to provide some salient features of innate programing and memory, patho-physiological consequences, underlying mechanisms, and current pressing issues.

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Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization

Cited by 158 publications

References 56 publications

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

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

Dynamic modulation of innate immunity programming and memory

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