Browsing by Author "Chen, Keqiang"

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    Alteration of Lysosome Fusion and Low-grade Inflammation Mediated by Super-low-dose Endotoxin
    Baker, Bianca; Geng, Shuo; Chen, Keqiang; Diao, Na; Yuan, Ruoxi; Xu, Xiguang; Dougherty, Sean; Stephenson, Caroline; Xiong, Huabao; Chu, Hong Wei; Li, Liwu (American Society for Biochemistry and Molecular Biology, Inc, 2015-01-13)
    Background: Super-low-dose endotoxemia contributes to cell stress and low-grade inflammation. Results: Super-low-dose LPS removed Tollip from late endosomes/lysosomes and blocked lysosome fusion with endosomes or autophagosomes. Tollip knock-out mice had impaired wound healing. Conclusion: Super-low-dose LPS leads to cell stress through clearing Tollip and blocking lysosome fusion. Significance: Our data reveal molecular dynamics of innate immunity regulation.
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    Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic Colitis
    Diao, Na; Zhang, Yao; Chen, Keqiang; Yuan, Ruoxi; Lee, Christina K.; Geng, Shuo; Kowalski, Elizabeth A.; Li, Liwu (Nature, 2016-10-05)
    Functionally compromised neutrophils contribute to adverse clinical outcomes in patients with severe inflammation and injury such as colitis and sepsis. However, the ontogeny of dysfunctional neutrophil during septic colitis remain poorly understood. We report that the dysfunctional neutrophil may be derived by the suppression of Toll-interacting-protein (Tollip). We observed that Tollip deficient neutrophils had compromised migratory capacity toward bacterial product fMLF due to reduced activity of AKT and reduction of FPR2, reduced potential to generate bacterial-killing neutrophil extra-cellular trap (NET), and compromised bacterial killing activity. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. The inflamed and incompetent neutrophil phenotype was also observed in vivo in Tollip deficient mice subjected to DSSinduced colitis. We observed that TUDCA, a compound capable of restoring Tollip cellular function, can potently alleviate the severity of DSS-induced colitis. In humans, we observed significantly reduced Tollip levels in peripheral blood collected from human colitis patients as compared to blood samples from healthy donors. Collectively, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.
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    Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M.
    Rothschild, Daniel E.; Zhang, Yao; Diao, Na; Lee, Christina K.; Chen, Keqiang; Caswell, Clayton C.; Slade, Daniel J.; Helm, Richard F.; LeRoith, Tanya; Li, Liwu; Allen, Irving C. (2016-12-03)
    Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m(-/-) mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m(-/-) animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m(-/-) mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m(-/-) mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.
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    Enhanced Neutrophil Immune Homeostasis Due to Deletion of PHLPP
    Ran, Taojing; Zhang, Yao; Diao, Na; Chen, Keqiang; Lee, Christina K.; Li, Liwu (Frontiers, 2019-09-06)
    Enhanced Neutrophil Immune Homeostasis Due to Deletion of PHLPNeutrophils are known to adopt dynamic and distinct functional phenotypes involved in the modulation of inflammation and immune homeostasis. However, inter-cellular signaling mechanisms that govern neutrophil polarization dynamics are not well understood. Employing a novel model of PHLPP deficient mice, we examined how neutrophils deficient in PHLPP may uniquely modulate immune defense and the host response during acute colitis. We found that PHLPP−/− mice were protected from dextran sodium sulfate (DSS)-induced septic colitis characterized by minimal body weight-loss, alleviated colon tissue destruction and reduced clinical symptoms. PHLPP−/− neutrophils have enhanced immune homeostasis as compared to WT neutrophils, reflected in enhanced migratory capacity toward chemoattractants, and reduced expression of inflammatory mediators due to elevated phosphorylation of AKT, STAT1, and ERK. Further, adoptive transfer of PHLPP deficient neutrophils to WT mice is sufficient to potently alleviate the severity of DSS-induced colitis. Our data reveal that PHLPP deficient neutrophils can be uniquely reprogrammed to a state conducive to host inflammation resolution. As a consequence, PHLPP−/− neutrophils can effectively transfer immune homeostasis in mice subjected to acute colitis. Our findings hold significant and novel insights into the mechanisms by which neutrophils can be effectively reprogrammed into a homeostatic state conducive for treating acute injuries such as septic colitis.
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    The persistence of low-grade inflammatory monocytes contributes to aggravated Atherosclerosis
    Geng, Shuo; Chen, Keqiang; Yuan, Ruoxi; Maitra, Urmila; Na, Diao; Chen, Chun; Zhang, Yao; Li, Liwu; Xiong, Huabao; Peng, Liang; Hu, Yuan; Qi, Chen-Feng; Pierce, Susan; Ling, Wenhua (Nature, 2016-11-08)
    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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    Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
    Chen, Keqiang; Yuan, Ruoxi; Zhang, Yao; Geng, Shuo; Li, Liwu (Wolters Kluwer Health, 2017-04-10)
    Background Compromised lipophagy with unknown mechanisms may be critically involved in the intracellular accumulation of lipids, contributing to elevated atherosclerosis and liver steatosis. We hypothesize that toll‐interacting protein (Tollip), a key innate immune molecule involved in the fusion of autolysosome, may play a significant role in lipophagy and modulate lipid accumulation during the pathogenesis of atherosclerosis and liver steatosis. Methods and Results By comparing mice fed with either a Western high‐fat diet or a regular chow diet, we observed that both atherosclerosis and liver steatosis were aggravated in apolipoprotein E–deficient (ApoE−/−)/Tollip−/− mice as compared with ApoE−/− mice. Through electron microscopy analyses, we observed compromised fusion of lipid droplets with lysosomes within aortic macrophages as well as liver hepatocytes from ApoE−/−/Tollip−/− mice as compared with ApoE−/− mice. As a molecular indicator for disrupted lysosome fusion, the levels of p62 were significantly elevated in aortic and liver tissues from ApoE−/−/Tollip−/− mice. Molecules involved in facilitating lipophagy completion such as Ras‐related protein 7 and gamma‐aminobutyric acid receptor‐associated protein were reduced in ApoE−/−/Tollip−/− mice as compared with ApoE−/− mice. Intriguingly, ApoE−/−/Tollip−/− mice had reduced circulating levels of inflammatory cytokines such as tumor necrosis factor‐α and increased levels of transforming growth factor‐β. The reduced inflammation due to Tollip deficiency is consistent with a stable atherosclerotic plaque phenotype with increased levels of plaque collagen and smooth muscle cells in ApoE−/−/Tollip−/− mice. Conclusions Tollip deficiency selectively leads to enlarged yet stable atherosclerotic plaques, increased circulating lipids, liver steatosis, and reduced inflammation. Compromised lipophagy and reduced expression of inflammatory mediators due to Tollip deficiency may be the underlying causes. Our data suggest that lipid accumulation and inflammation may be intertwined yet independent processes during the progression of atherosclerosis and steatosis.