TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection

Wang, Zhaojun; Fayngerts, Svetlana; Wang, Peng; Sun, Honghong; Johnson, Derek; Ruan, Qingguo; Guo, Wei; Chen, Youhai H.

doi:10.1073/pnas.1204525109

Cited by 87 publications

(115 citation statements)

References 26 publications

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“…Upon treatment with ox-LDL, the DCF fluorescence levels were upregulated markedly in macrophages with TIPE2 2/2 genotype compared with WT controls, suggesting that TIPE2 expression in macrophages inhibits ROS generation. This result coincides with the notion that TIPE2 serves as a negative regulator of oxidative burst during infection (13). Recent studies suggest that HO-1, a rate-limiting enzyme in the catabolism of heme, plays an antiatherosclerotic role by reducing ferritin and sequestering Fe, which is an important catalyst for ROS formation (21,31,32).…”

Section: Discussionsupporting

confidence: 71%

“…One day before transplantation, Ldlr 2/2 (age 11 wk, n = 16; purchased from Model Animal Research Center of Nanjing University, Nanjing, China) mice were subjected to lethal irradiation with 1000 rad (10 Gy) to eliminate bone marrow stem cells. Donor bone marrow from 11-wk-old TIPE2 2/2 mice (n = 6, as previously described [8,11,13]) in C57BL/6J background or age-and sexmatched wild type (WT; C57BL/6J background; n = 6) was prepared by flushing the femur and tibia as previously described (17). For transplantation, recipient mice were injected with 5 3 10 6 bone marrow cells through the tail vein.…”

Section: Animals and Bone Marrow Transplantationmentioning

confidence: 99%

“…Early studies show that TIPE2 plays an essential role in the maintenance of immune homeostasis (8). TIPE2 can regulate both inflammation and carcinogenesis (8,11) Interestingly, it is found highly expressed in macrophages and serves as a negative regulator of innate immunity through inhibiting TLR signaling (8,12,13). Its germline deletion leads to fatal inflammatory diseases, and abnormal expression of TIPE2 in humans was found to be associated with hepatitis B, diabetic nephropathy, and experimental stroke (8,(14)(15)(16).…”

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confidence: 99%

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Enhanced Atherosclerosis in TIPE2-Deficient Mice Is Associated with Increased Macrophage Responses to Oxidized Low-Density Lipoprotein

Lou

Liu

Zhang

et al. 2013

The Journal of Immunology

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Atherosclerosis has been widely recognized as an inflammatory disease of the arterial wall in which macrophages play a major role. Yet, how macrophage-mediated pathology is regulated during atherosclerosis is poorly understood. TNF-α–induced protein 8–like 2 (TIPE2, also known as TNFAIP8L2) is highly expressed in resting macrophages and can negatively regulate inflammation through inhibiting immune receptor signaling. We report in this article that TIPE2 plays a crucial atheroprotective role likely by regulating macrophage responses to oxidized low-density lipoprotein (ox-LDL). TIPE2-deficient macrophages treated with ox-LDL produced more oxidative stress and proinflammatory cytokines, and exhibited heightened activation of the JNK, NF-κB, and p38 signaling pathways. As a consequence, TIPE2 deficiency in bone marrow–derived cells exacerbated atherosclerosis development in Ldlr−/− mice fed a high-fat diet. Importantly, ox-LDL markedly downregulated TIPE2 mRNA and protein levels in macrophages, suggesting that ox-LDL mediates atherosclerosis by TIPE2 inhibition. These results indicate that TIPE2 is a new inhibitor of atherosclerosis and a potential drug target for treating the disease.

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Section: Discussionsupporting

confidence: 71%

Section: Animals and Bone Marrow Transplantationmentioning

confidence: 99%

mentioning

confidence: 99%

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Enhanced Atherosclerosis in TIPE2-Deficient Mice Is Associated with Increased Macrophage Responses to Oxidized Low-Density Lipoprotein

Lou

Liu

Zhang

et al. 2013

The Journal of Immunology

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“…72 TIPE2 is also a negative regulator of phagocytosis and oxidative burst induced by TLRs, and knockout mice were found to be resistant to bacterial infections. 73 Similarly, the loss of TIPE2 led to increased induced nitric oxide production by macrophages upon LPS stimulation. 74 TIPE2 may also be a negative inhibitor of atherosclerosis formation because TIPE2 inhibited smooth muscle proliferation and differentiation, whereas TIPE2 deficiency accelerated neointima formation.…”

Section: Tipe2 Is a Negative Regulator Of Immunity And Inflammationmentioning

confidence: 99%

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Goldsmith

Chen

2017

Cell Mol Immunol

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The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation. An expression analysis in humans demonstrated that the TIPE family is dysregulated in cancer and inflammation, and studies both in mice and in vitro have demonstrated that this family of proteins plays a critical role in tumorigenesis and inflammatory responses. In this review, we summarize the current literature for all four family members, with a special focus on the phenotypic manifestations present in the various knockout murine strains, as well as the related cell signaling that has been elucidated to date.

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“…The phagocytosis was calculated by normalizing with the phagocytosis at 4°C. The phagocytosis index was calculated as described previously (36).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages

Saha¹,

Momen-Heravi²,

Kodys

et al. 2016

Journal of Biological Chemistry

186

155

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Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals.Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration-and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGF␤ and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcoholexposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages.

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TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection

Cited by 87 publications

References 26 publications

Enhanced Atherosclerosis in TIPE2-Deficient Mice Is Associated with Increased Macrophage Responses to Oxidized Low-Density Lipoprotein

Enhanced Atherosclerosis in TIPE2-Deficient Mice Is Associated with Increased Macrophage Responses to Oxidized Low-Density Lipoprotein

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages

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