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Shanmugam, Nanda

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Shanmugam

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Nanda

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Shanmugam, Nanda
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    Commensal Bacteria-Induced Inflammasome Activation in Mouse and Human Macrophages Is Dependent on Potassium Efflux but Does Not Require Phagocytosis or Bacterial Viability
    (Public Library of Science, 2016) Chen, Kejie; Shanmugam, Nanda; Pazos, Michael A.; Hurley, Bryan; Cherayil, Bobby
    Gut commensal bacteria contribute to the pathogenesis of inflammatory bowel disease, in part by activating the inflammasome and inducing secretion of interleukin-1Ăź (IL-1Ăź). Although much has been learned about inflammasome activation by bacterial pathogens, little is known about how commensals carry out this process. Accordingly, we investigated the mechanism of inflammasome activation by representative commensal bacteria, the Gram-positive Bifidobacterium longum subspecies infantis and the Gram-negative Bacteroides fragilis. B. infantis and B. fragilis induced IL-1Ăź secretion by primary mouse bone marrow-derived macrophages after overnight incubation. IL-1Ăź secretion also occurred in response to heat-killed bacteria and was only partly reduced when phagocytosis was inhibited with cytochalasin D. Similar results were obtained with a wild-type immortalized mouse macrophage cell line but neither B. infantis nor B. fragilis induced IL-1Ăź secretion in a mouse macrophage line lacking the nucleotide-binding/leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome. IL-1Ăź secretion in response to B. infantis and B. fragilis was significantly reduced when the wild-type macrophage line was treated with inhibitors of potassium efflux, either increased extracellular potassium concentrations or the channel blocker ruthenium red. Both live and heat-killed B. infantis and B. fragilis also induced IL-1Ăź secretion by human macrophages (differentiated THP-1 cells or primary monocyte-derived macrophages) after 4 hours of infection, and the secretion was inhibited by raised extracellular potassium and ruthenium red but not by cytochalasin D. Taken together, our findings indicate that the commensal bacteria B. infantis and B. fragilis activate the NLRP3 inflammasome in both mouse and human macrophages by a mechanism that involves potassium efflux and that does not require bacterial viability or phagocytosis.
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    Tumor Necrosis Factor \(\alpha\) Inhibits Expression of the Iron Regulating Hormone Hepcidin in Murine Models of Innate Colitis
    (Public Library of Science, 2012) Shanmugam, Nanda; Ellenbogen, Shiri; Trebicka, Estela; Wang, Lijian; Mukhopadhyay, Subhankar; Lacy-Hulbert, Adam; Gallini, Carey; Garrett, Wendy; Cherayil, Bobby
    Background: Abnormal expression of the liver peptide hormone hepcidin, a key regulator of iron homeostasis, contributes to the pathogenesis of anemia in conditions such as inflammatory bowel disease (IBD). Since little is known about the mechanisms that control hepcidin expression during states of intestinal inflammation, we sought to shed light on this issue using mouse models. Methodology/Principal Findings: Hepcidin expression was evaluated in two types of intestinal inflammation caused by innate immune activation—dextran sulfate sodium (DSS)-induced colitis in wild-type mice and the spontaneous colitis occurring in T-bet/Rag2-deficient (TRUC) mice. The role of tumor necrosis factor (TNF) \(\alpha\) was investigated by in vivo neutralization, and by treatment of a hepatocyte cell line, as well as mice, with the recombinant cytokine. Expression and activation of Smad1, a positive regulator of hepcidin transcription, were assessed during colitis and following administration or neutralization of TNF\(\alpha\). Hepcidin expression progressively decreased with time during DSS colitis, correlating with changes in systemic iron distribution. TNF\(\alpha\) inhibited hepcidin expression in cultured hepatocytes and non-colitic mice, while TNF\(\alpha\) neutralization during DSS colitis increased it. Similar results were obtained in TRUC mice. These effects involved a TNF\(\alpha\)-dependent decrease in Smad1 protein but not mRNA. Conclusions/Significance: TNF\(\alpha\) inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process. This inhibitory effect of TNF\(\alpha\) may be superseded by other factors in the context of T cell-mediated colitis given that in the latter form of intestinal inflammation hepcidin is usually up-regulated.