bims-stacyt Biomed news
on Starvation pathways leading to cytokine regulation
Issue of 2018‒06‒03
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Brain Res. 2018 May 24. pii: S0006-8993(18)30293-2. [Epub ahead of print]
    Wang Z, Zhou Y, Yu Y, He K, Cheng LM.
      BACKGROUND: The inflammatory reaction of the spleen is an important component in the pathophysiology of cerebral ischaemia (CI). Regulatory B cells (Bregs) derived from the spleen can inhibit the expansion of inflammation and reduce the damage caused by CI.AIM: The aim of the present study was to explore changes in spleen function and Bregs production due to lipopolysaccharide preconditioning (LPS PC) in ischaemia/reperfusion (I/R) and to uncover potential protective effect of LPS PC on stroke.
    METHODS: Focal cerebral I/R mice were induced by middle cerebral artery occlusion (MCAO). Infarct size and inflammatory cell infiltration in brain tissue, athletic ability, and immune status were analysed by immunostaining, behavioural analyses, and flow cytometry, respectively.
    RESULTS: The volume of the cerebral infarct was significantly decreased in I/R mice with LPS PC (LPS+I/R) compared to I/R mice, and neuronal apoptosis was ameliorated by LPS PC. After preconditioning with LPS, locomotor activity, forelimb strength, motor endurance, motor coordination, and short-term memory were improved to varying degrees. Moreover, blood-brain barrier (BBB) dysfunction was reversed, and CD11b+, major histocompatibility complex-II positive (MHC-II+), and Gr-1+ cell infiltration in the brains of LPS+I/R mice was also significantly reduced. B cell-activating factor (BAFF), tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 in the brain and spleen in the LPS+I/R group decreased to different degrees, while the levels of transforming growth factor-β (TGF-β) and IL-10 increased. LPS PC alleviated atrophy of the spleen following I/R. In addition, the number of CD8+ T cells, macrophages, TNF+ cells, NF-κB + cells, and neutrophils in the spleen was reduced, while the number of proliferating cells and CD19+-IL10+ Bregs was significantly increased. The number of follicular B (FO B) cells and marginal zone B (MZ B) cells in the spleens of LPS+I/R mice was also increased.
    CONCLUSIONS: I/R mice preconditioned with LPS showed significantly reduced pathological damage, motor dysfunction, cognitive dysfunction, and inflammatory responses. LPS PC may initiate anti-inflammatory protective mechanism in the spleen after stroke, may increase the number of anti-inflammatory cells, such as Bregs, in the spleen, and may play a protective role in stroke.
    Keywords:  IL-10; Inflammation; Ischaemia/reperfusion; Lipopolysaccharide; Regulatory B cells; Spleen
    DOI:  https://doi.org/10.1016/j.brainres.2018.05.036
  2. Cancer Lett. 2018 May 23. pii: S0304-3835(18)30364-1. [Epub ahead of print]430 160-171
    Thongchot S, Ferraresi A, Vidoni C, Loilome W, Yongvanit P, Namwat N, Isidoro C.
      Cholangiocarcinoma (CCA), the cancer arising from the epithelial cells of bile ducts, is a prototype of inflammatory-driven cancer. Cytokines released by cancer associated fibroblasts (CAFs) play a pivotal role in CCA progression, driving the epigenetic Epithelial-to-Mesenchymal transition and the growth and metastasization of CCA cells. Consistently, the conditioned medium from CCA-derived CAFs further stimulated the secretion of IL-6, and to a lesser extent of IL-8, by CCA cells. CCA has a poor prognosis, because of late diagnosis and of high resistance to radio- and chemo-therapy of CCA cells. Targeting the CAFs and their secretion could be an alternative option. We found that while IL-6 indeed promoted the cell migration of invasive CCA cells, the nutraceutical Resveratrol strongly counteracted this effect both in CCA cells and in immortalized cholangiocytes. More importantly, here we show that Resveratrol has the potential to abrogate the secretion of IL-6 by CAFs. While the conditioned medium from CAFs strongly induced IL-6 mediated motility of CCA cells, the conditioned medium from CAFs pre-treated with Resveratrol completely halted cancer cell motility and reverted the N-to E-cadherin switch in migrating cells. This effect was associated with stimulation of autophagy in the cancer cells. This is the first demonstration that CAFs secretory products directly affect the regulation of autophagy and consequently the behavior of CCA cells, and that a nutraceutical may revert the malignant phenotype of cancer cells by acting on CAFs metabolism and secretion.
    Keywords:  Autophagy; Cadherins; Cancer associated fibroblasts; Cancer therapy; Cholangiocarcinoma; Cytokines; Desmoplastic stroma; Nutraceuticals; Resveratrol; Tumor invasion
    DOI:  https://doi.org/10.1016/j.canlet.2018.05.031
  3. Eur J Nutr. 2018 May 26.
    Nimri L, Grajeda-Iglesias C, Volkova N, Aviram M.
      PURPOSE: Obesity, which is characterized by triglyceride accumulation mainly in adipocytes but also in arterial wall cells such as macrophages, is a major risk factor for developing atherosclerosis. We aimed to identify the crosstalk related to lipid metabolism and oxidation status between adipocytes and macrophages.METHODS: We used a co-culture model system with J477A.1 cultured macrophages and 3T3L1 cultured adipocytes. For an in-vivo co-culture system, we used C57BL/6 mouse peritoneal macrophages and visceral or subcutaneous adipose tissue.
    RESULTS: Adipocytes significantly increased reactive oxygen species generation, up to twofold, and decreased cholesterol content by 22% in the co-cultured macrophages. Macrophages significantly increased triglyceride-biosynthesis rate by twofold and decreased triglyceride-degradation rate by 30%, resulting in increased triglyceride accumulation in the co-cultured adipocytes by up to 72%. In the in-vivo mouse model, visceral adipose tissue crosstalk with macrophages resulted in a significant pro-atherogenic phenotype with respect to cellular cholesterol metabolism. In contrast, the interaction between subcutaneous adipose tissue and macrophages mostly affected cellular triglyceride metabolism. There were no significant effects on mitochondrial respiration capacity in the macrophages. Upon oxidative-stress reduction in the co-cultured cells using the polyphenol-rich antioxidant, pomegranate juice, the expression of genes related to cellular lipid accumulation was significantly reduced.
    CONCLUSIONS: We reveal, for the first time, that paracrine interactions between adipocytes and macrophages result in oxidative stress and lipids metabolic alterations in both cells, toward increased atherogenicity which can be reversed by phenolic antioxidants.
    Keywords:  Adipocyte; Atherogenicity; Co-culture; Crosstalk; Macrophage
    DOI:  https://doi.org/10.1007/s00394-018-1729-7
  4. Exp Cell Res. 2018 May 24. pii: S0014-4827(18)30298-2. [Epub ahead of print]
    Geng W, Qin F, Ren J, Xiao S, Wang A.
      Endoplasmic reticulum (ER) stress signaling is activated in retinal degeneration disease. Activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response (UPR), is a key element that maintains cell survival and proliferation in hypoxic conditions. Our previous studies showed that a small ribosomal protein L41 (RPL41) inhibits ATF4 by inducing its phosphorylation and degradation. In the present study, the effects of mini-peptide RPL41 on retinal neovascularization (RNV) in oxygen-induced retinopathy (OIR) mice was investigated. We induced OIR in C57BL/6 mice and obtained retinas from normoxia, OIR, OIR control (treated with PBS), and OIR treated (treated with RPL41) mice. Our results showed that ER stress signaling was activated and ATF4 was overexpressed in the retinas of OIR mice. After intravitreal injection of RPL41, the size of RNV and vaso-obliteration, and the number of preretinal neovascular cell nuclei in the retinas of OIR mice were significantly decreased. Western blot analysis and quantitative real-time polymerase chain reaction (qPCR) showed ATF4 and VEGF expression decreased after intravitreal injection of RPL41. Furthermore, the expression levels of inflammatory genes including TNF-α, IL-1β, and IL-6 were significantly decreased compared with the OIR control mice. In conclusion, RPL41 prevented pathologic neovascularization and exerted anti-inflammatory effects by degrading the important ER stress factor ATF4, thus, RPL41 could be a promising therapeutic agent for the treatment of neovascular eye diseases, especially retinopathy of prematurity (ROP).
    Keywords:  ER stress; Ribosomal protein L41; activating transcription 4; neovascular; oxygen induced retinopathy
    DOI:  https://doi.org/10.1016/j.yexcr.2018.05.027
  5. Pathol Res Pract. 2018 May 20. pii: S0344-0338(18)30063-3. [Epub ahead of print]
    Cui G, Yuan A, Sun Z, Zheng W, Pang Z.
      OBJECTIVES: Recent studies suggest that the interaction between interleukin (IL)-1β and IL-6 in the microenvironment might be involved in the development and progression of human colorectal cancer (CRC). However, the expression of IL-1β/IL-6 network within the CRC microenvironment is not fully understood.MATERIALS AND METHODS: The level of IL-1β/IL-6 network expression in 40 biopsies of sporadic CRC and 15 biopsies of controls was assessed using quantitative real-time polymerase chain reaction (PCR) assay, immunohistochemistry (IHC) and double immunofluorescence staining.
    RESULTS: Quantitative results obtained by real-time PCR revealed that both IL-1β and IL-6 mRNA expressions were increased in CRC tissues compared with expressions in controls. In which, IL-6 mRNA expression in primary CRC tissues showed a statistically significant relationship with tumor invasion depth. IHC observations confirmed that increased expression of IL-1β and IL-6 immunoreactivities was located in both the CRC epithelium and stroma. Furthermore, IHC results also revealed that increased expression of IL-1β receptor type 1 (IL-1R1) and IL-6 receptor (IL-6R) were observed in both CRC epithelial and stromal cells. IHCs in serial CRC sections and double immunofluorescence staining revealed a highly co-expression of IL-1R1 immunoreactivity with IL-6 immunoreactivity in the same cells, which confirmed a histological fundament of IL-1β/IL-6 network.
    CONCLUSION: The IL-1β/IL-6 network is highly expressed in the CRC microenvironment, indicating that this network is important in the progression of CRC.
    Keywords:  Carcinogenesis; Colorectum; Interleukin-1β; Interlukin-6
    DOI:  https://doi.org/10.1016/j.prp.2018.05.011
  6. Am J Pathol. 2018 May 24. pii: S0002-9440(18)30223-2. [Epub ahead of print]
    Li Y, Chao X, Yang L, Lu Q, Li T, Ding WX, Ni HM.
      Lipid droplets (LDs) are intracellular organelles that store neutral lipids as energy reservoir. Recent studies suggest that autophagy is important in maintaining the homeostasis of intracellular LDs by either regulating the biogenesis of LDs, mobilization of fatty acids, or degradation of LDs in cultured cells. Increasing evidence also supports a role of autophagy in regulating glucose and lipid metabolism in vivo in mammals. In response to fasting/starvation, lipids are mobilized from the adipose tissue to the liver, which increases the number of intracellular LDs and stimulates fatty acid oxidation and ketogenesis. However, it is still controversial and unclear how impaired autophagy in hepatocytes affects the biogenesis of LDs in mouse livers. In the present study, we demonstrated that hepatic autophagy-deficient mice (L-Atg5 KO mice) had impaired adaptation to fasting-induced hepatic biogenesis of LDs. The maladaptation to fasting-induced hepatic biogenesis of LDs in L-Atg5 KO mouse livers was not due to hepatic changes of de novo lipogenesis, secretion of very-low-density lipoprotein or fatty acid β-oxidation, but was due to persistent Nrf2 activation because biogenesis of LDs restored in L-Atg5/Nrf2 double-knockout mice.
    DOI:  https://doi.org/10.1016/j.ajpath.2018.04.015
  7. Fish Shellfish Immunol. 2018 May 24. pii: S1050-4648(18)30310-3. [Epub ahead of print]
    Dai WF, Zhang JJ, Qiu QF, Chen J, Yang W, Ni S, Xiong JB.
      Aquatic animals are frequently suffered from starvation due to restricted food availability or deprivation. It is currently known that gut microbiota assists host in nutrient acquisition. Thus, exploring the gut microbiota responses would improve our understanding on physiological adaptation to starvation. To achieve this, we investigated how the gut microbiota and shrimp digestion and immune activities were affected under starvation stress. The results showed that the measured digestion activities in starved shrimp were significantly lower than in normal cohorts; while the measured immune activities exhibited an opposite trend. A structural equation modeling (SEM) revealed that changes in the gut bacterial community were directly related to digestive and immune enzyme activities, which in turn markedly affected shrimp growth traits. Notably, several gut bacterial indicators that characterized the shrimp nutrient status were identified, with more abundant opportunistic pathogens in starved shrimp, although there were no statistical differences in the overall diversity and the structures of gut bacterial communities between starved and normal shrimp. Starved shrimp exhibited less connected and cooperative interspecies interaction as compared with normal cohorts. Additionally, the functional pathways involved in carbohydrate and protein digestion, glycan biosynthesis, lipid and enzyme metabolism remarkably decreased in starved shrimp. These attenuations could increase the susceptibility of starved shrimp to pathogens infection. In summary, this study provides novel insights into the interplay among shrimp digestion, immune activities and gut microbiota in response to starvation stress.
    Keywords:  Functional pathways; Immune activity; Interspecies interaction; Shrimp gut microbiota; Starvation stress
    DOI:  https://doi.org/10.1016/j.fsi.2018.05.040