bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒03‒01
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Mediators Inflamm. 2020 ;2020 6357046
    Dewitte A, Villeneuve J, Lepreux S, Bouchecareilh M, Gauthereau X, Rigothier C, Combe C, Ouattara A, Ripoche J.
      Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.
    DOI:  https://doi.org/10.1155/2020/6357046
  2. Dev Cell. 2020 Feb 12. pii: S1534-5807(20)30063-0. [Epub ahead of print]
    Sullivan GP, O'Connor H, Henry CM, Davidovich P, Clancy DM, Albert ML, Cullen SP, Martin SJ.
      Inflammation triggered by infection or cellular necrosis is initiated by a battery of pattern-recognition receptors, such as Toll-like receptors or IL-1 family receptors. Diverse forms of cell stress, such as ER stress or mitochondrial stress, can also promote inflammatory responses that contribute to the chronic inflammation observed in cancer, obesity, and other conditions. However, the molecular mechanisms of cell-stress-induced inflammation are poorly understood. Here, we show that ER stress initiated NF-κB activation and inflammation through transcriptional upregulation and ligand-independent activation of TRAIL receptors. ER-stress-induced TRAIL receptor activation resulted in caspase-8/FADD/RIPK1-dependent NF-κB activation and inflammatory cytokine production. Silencing or deletion of TRAIL receptors, or their downstream effectors caspase-8, FADD, or RIPK1, suppressed ER-stress-induced inflammation. Furthermore, chemotherapeutic stress-induced inflammatory responses were blunted in DR5/TRAIL-R null animals. We propose that, upon ER stress, TRAIL receptors serve as "stress-associated molecular patterns (SAMPs)" coupling ER stress to NF-κB-dependent inflammation.
    Keywords:  DR4; DR5; ER Stress; NF-κB; RIPK1; SAMP; TRAIL; death receptors; inflammation; taxol
    DOI:  https://doi.org/10.1016/j.devcel.2020.01.031
  3. JCI Insight. 2020 Feb 27. pii: 131870. [Epub ahead of print]
    Laurens C, Parmar A, Murphy E, Carper D, Lair B, Maes P, Vion J, Boulet N, Fontaine C, Marqués MA, Larrouy D, Harant I, Thalamas C, Montastier E, Caspar-Bauguil S, Bourlier V, Tavernier G, Grolleau JL, Bouloumié A, Langin D, Viguerie N, Bertile F, Blanc S, de Glisezinski I, O'Gorman DJ, Moro C.
      We hypothesized that skeletal muscle contraction produces a cellular stress signal triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying novel exercise-regulated myokines, also known as exerkines, able to promote lipolysis.Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. Conditioned media and human plasma samples were analyzed using unbiased proteomic and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples.CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes (1.3 to 8 fold, p<0.001). Growth and Differentiation Factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was up-regulated in CM from both acute and chronic exercise-stimulated myotubes. We further show that physiological concentrations of recombinant GDF15 protein increase lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogates EPS CM-mediated lipolysis.We herein provide the first evidence that GDF15 is a novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
    Keywords:  Adipose tissue; Metabolism; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.131870
  4. J Biol Chem. 2020 Feb 27. pii: jbc.RA119.012419. [Epub ahead of print]
    Abbadi A, Loftis J, Wang A, Yu M, Wang Y, Shakya S, Li X, Maytin EV, Hascall VC.
      Monocytes are rapidly recruited to sites of diabetic complications and differentiate into macrophages. Previously, we showed that rat kidney mesangial cells dividing during hyperglycemic stress abnormally synthesize hyaluronan (HA) in intracellular compartments. This initiates a stress response resulting in an extracellular HA matrix after division that recruits inflammatory cells. Cell-cell communication among macrophages that are recruited into the glomeruli and the damaged rat mesangial cells leads to diabetic nephropathy, fibrosis, and proteinurea, which are inhibited in heparin-treated diabetic rats. In this study, we found that murine bone marrow-derived macrophages (BMDMs) and a human leukemic cell line, U937cells, dividing in hyperglycemia also accumulate intracellular HA and that heparin inhibits the HA accumulation. Both cell types expressed increased levels of pro-inflammatory markers - inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α)- when cultured under hyperglycemic stress, which was inhibited by heparin. Furthermore, the abnormal intracellular HA was also observed in peripheral blood monocytes derived from three different hyperglycemic diabetic mouse models - streptozotocin treated, high-fat fed and Ins2Akita. Moreover, peripheral blood monocytes in humans with type 2 diabetes and poorly controlled blood glucose levels (hemoglobin A1c (HbA1c) levels >7) also had intracellular HA, whereas those with HbA1c <7, did not.  Of note, heparin increased the anti-inflammatory markers arginase 1 (ARG1) and interleukin-10 (IL-10) in murine BMDMs. We conclude that heparin treatment of high glucose-exposed dividing BMDMs promotes an anti-inflammatory tissue-repair phenotype in these cells.
    Keywords:  heparin; hyaluronan; inflammation; macrophage; monocyte
    DOI:  https://doi.org/10.1074/jbc.RA119.012419