Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Erratum in : Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR. [Cell. 2019]International audienceInnate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-likereceptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatorysignals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect theimmune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DC)are exacerbated by a high fatty acid (FA) metabolic environment. FA suppress the TLR-inducedhexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changesenhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded proteinresponse (UPR) leading to a distinct transcriptomic signature, with IL-23 as hallmark. Interestingly,chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response.Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innateimmunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR

Innate immunity based cancer immunotherapy: B16-F10 murine melanoma model

Abstract Background Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19th century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. Methods B16-F10 murine melanoma model was used. For the stimulation of phagocytosis, mannan or N-formyl-methionyl-leucyl-phenylalanine, was covalently bound to tumor cells or attached using hydrophobic anchor. The following agonists of Toll-like receptors were studied: monophosphoryl lipid A (MPLA), imiquimod (R-837), resiquimod (R-848), poly(I:C), and heat killed Listeria monocytogenes. Results R-848 proved to be the most suitable Toll-like receptor agonist for our novel immunotherapeutic approach. In combination with covalently bound mannan, R-848 significantly reduced tumor growth. Adding poly(I:C) and L. monocytogenes resulted in complete recovery in 83% of mice and in their protection from the re-transplantation of melanoma cells. Conclusion An efficient cancer treatment results from the combination of Toll-like receptor agonists and phagocytosis stimulating ligands bound to the tumor cells.http://deepblue.lib.umich.edu/bitstream/2027.42/134739/1/12885_2016_Article_2982.pd

Punicic Acid a Conjugated Linolenic Acid Inhibits TNFα-Induced Neutrophil Hyperactivation and Protects from Experimental Colon Inflammation in Rats

BACKGROUND:Neutrophils play a major role in inflammation by releasing large amounts of ROS produced by NADPH-oxidase and myeloperoxidase (MPO). The proinflammatory cytokine TNFalpha primes ROS production through phosphorylation of the NADPH-oxidase subunit p47phox on Ser345. Conventional anti-inflammatory therapies remain partially successful and may have side effects. Therefore, regulation of neutrophil activation by natural dietary components represents an alternative therapeutic strategy in inflammatory diseases such as inflammatory bowel diseases. The aim of this study was to assess the effect of punicic acid, a conjugated linolenic fatty acid from pomegranate seed oil on TNFalpha-induced neutrophil hyperactivation in vitro and on colon inflammation in vivo. METHODOLOGY AND PRINCIPAL FINDINGS:We analyzed the effect of punicic acid on TNFalpha-induced neutrophil upregulation of ROS production in vitro and on TNBS-induced rat colon inflammation. Results show that punicic acid inhibited TNFalpha-induced priming of ROS production in vitro while preserving formyl-methionyl-leucyl-phenylalanine (fMLP)-induced response. This effect was mediated by the inhibition of Ser345-p47phox phosphorylation and upstream kinase p38MAPK. Punicic acid also inhibited fMLP- and TNFalpha+fMLP-induced MPO extracellular release from neutrophils. In vivo experiments showed that punicic acid and pomegranate seed oil intake decreased neutrophil-activation and ROS/MPO-mediated tissue damage as measured by F2-isoprostane release and protected rats from TNBS-induced colon inflammation. CONCLUSIONS/SIGNIFICANCE:These data show that punicic acid exerts a potent anti-inflammatory effect through inhibition of TNFalpha-induced priming of NADPH oxidase by targeting the p38MAPKinase/Ser345-p47phox-axis and MPO release. This natural dietary compound may provide a novel alternative therapeutic strategy in inflammatory diseases such as inflammatory bowel diseases

TGF-β-Mediated Sustained ERK1/2 Activity Promotes the Inhibition of Intracellular Growth of Mycobacterium avium in Epithelioid Cells Surrogates

Transforming growth factor beta (TGF-β) has been implicated in the pathogenesis of several diseases including infection with intracellular pathogens such as the Mycobacterium avium complex. Infection of macrophages with M. avium induces TGF-β production and neutralization of this cytokine has been associated with decreased intracellular bacterial growth. We have previously demonstrated that epithelioid cell surrogates (ECs) derived from primary murine peritoneal macrophages through a process of differentiation induced by IL-4 overlap several features of epithelioid cells found in granulomas. In contrast to undifferentiated macrophages, ECs produce larger amounts of TGF-β and inhibit the intracellular growth of M. avium. Here we asked whether the levels of TGF-β produced by ECs are sufficient to induce a self-sustaining autocrine TGF-β signaling controlling mycobacterial replication in infected-cells. We showed that while exogenous addition of increased concentration of TGF-β to infected-macrophages counteracted M. avium replication, pharmacological blockage of TGF-β receptor kinase activity with SB-431542 augmented bacterial load in infected-ECs. Moreover, the levels of TGF-β produced by ECs correlated with high and sustained levels of ERK1/2 activity. Inhibition of ERK1/2 activity with U0126 increased M. avium replication in infected-cells, suggesting that modulation of intracellular bacterial growth is dependent on the activation of ERK1/2. Interestingly, blockage of TGF-β receptor kinase activity with SB-431542 in infected-ECs inhibited ERK1/2 activity, enhanced intracellular M. avium burden and these effects were followed by a severe decrease in TGF-β production. In summary, our findings indicate that the amplitude of TGF-β signaling coordinates the strength and duration of ERK1/2 activity that is determinant for the control of intracellular mycobacterial growth

Meta-analysis of archived DNA microarrays identifies genes regulated by hypoxia and involved in a metastatic phenotype in cancer cells

<p>Abstract</p> <p>Background</p> <p>Metastasis is a major cancer-related cause of death. Recent studies have described metastasis pathways. However, the exact contribution of each pathway remains unclear. Another key feature of a tumor is the presence of hypoxic areas caused by a lack of oxygen at the center of the tumor. Hypoxia leads to the expression of pro-metastatic genes as well as the repression of anti-metastatic genes. As many Affymetrix datasets about metastasis and hypoxia are publicly available and not fully exploited, this study proposes to re-analyze these datasets to extract new information about the metastatic phenotype induced by hypoxia in different cancer cell lines.</p> <p>Methods</p> <p>Affymetrix datasets about metastasis and/or hypoxia were downloaded from GEO and ArrayExpress. AffyProbeMiner and GCRMA packages were used for pre-processing and the Window Welch <it>t </it>test was used for processing. Three approaches of meta-analysis were eventually used for the selection of genes of interest.</p> <p>Results</p> <p>Three complementary approaches were used, that eventually selected 183 genes of interest. Out of these 183 genes, 99, among which the well known <it>JUNB</it>, <it>FOS </it>and <it>TP63</it>, have already been described in the literature to be involved in cancer. Moreover, 39 genes of those, such as <it>SERPINE1 </it>and <it>MMP7</it>, are known to regulate metastasis. Twenty-one genes including <it>VEGFA </it>and <it>ID2 </it>have also been described to be involved in the response to hypoxia. Lastly, DAVID classified those 183 genes in 24 different pathways, among which 8 are directly related to cancer while 5 others are related to proliferation and cell motility. A negative control composed of 183 random genes failed to provide such results. Interestingly, 6 pathways retrieved by DAVID with the 183 genes of interest concern pathogen recognition and phagocytosis.</p> <p>Conclusion</p> <p>The proposed methodology was able to find genes actually known to be involved in cancer, metastasis and hypoxia and, thus, we propose that the other genes selected based on the same methodology are of prime interest in the metastatic phenotype induced by hypoxia.</p