bims-stacyt 2018-12-02 papers

Cytokine. 2018 Nov 21. pii: S1043-4666(18)30427-7. [Epub ahead of print]

Metabolic regulation of infection and inflammation.

Immunometabolic framework provides a way to understand the immune regulation via cell intrinsic metabolic fluxes and metabolites during infections, tumors, and inflammatory disorders. During these diseases, the immune cells are activated requiring more energy and moderating their metabolic functions. The two categories of metabolic alterations are therefore causally associated with energy derivation and cellular functions. Pathogens, tumors and inflammation target energy metabolism, primarily glucose uptake, glucose catabolism, gluconeogenesis for continuing lipid metabolism through mainstream pathways such as glycolysis, tricarboxylic acid cycle, mitochondrial respiration and pentose phosphate pathway. Many biosynthetic pathways such as those of cholesterol, ceramide, sphingolipids, and fatty acids are altered explaining the metabolic interface in molecular pathogenesis in various infectious and non-infectious inflammatory diseases. The emerging immune-metabolic framework also identifies the key regulatory elements such as metabolites, signalling intermediates and transcription factors. These regulatory elements play key roles in deciding the fate of an infection, tumor or autoimmune diseases. The original research articles and the review articles in this Special issue of Cytokine on "Infection, Inflammation and Immunometabolomes" highlight these aspects of metabolic reprogramming and the role of some 'metabolomic regulators' in controlling the outcome of infectious and non-infectious diseases. In this Editorial, we introduce the readers to these articles discussing the elements in immune-metabolic framework.

Keywords: Infection; Inflammation; Macrophage; Metabolism; T-cell

DOI: https://doi.org/10.1016/j.cyto.2018.11.016

Cell Physiol Biochem. 2018 Nov 26. 51(3): 1051-1068

Decreased TLR3 in Hyperplastic Adipose Tissue, Blood and Inflamed Adipocytes is Related to Metabolic Inflammation.

Jèssica Latorre, José M Moreno-Navarrete, Mónica Sabater, Maria Buxo, José I Rodriguez-Hermosa, Jordi Girones, José M Fort, Ramón Vilallonga, Wifredo Ricart, Rafael Simo, Jose-Manuel Fernandez-Real, Francisco J Ortega.

BACKGROUND/AIMS: Obesity is characterized by the immune activation that eventually dampens insulin sensitivity and changes metabolism. This study explores the impact of different inflammatory/ anti-inflammatory paradigms on the expression of toll-like receptors (TLR) found in adipocyte cultures, adipose tissue, and blood.METHODS: We evaluated by real time PCR the impact of acute surgery stress in vivo (adipose tissue) and macrophages (MCM) in vitro (adipocytes). Weight loss was chosen as an anti-inflammatory model, so TLR were analyzed in fat samples collected before and after bariatric surgery-induced weight loss. Associations with inflammatory and metabolic parameters were analyzed in non-obese and obese subjects, in parallel with gene expression measures taken in blood and isolated adipocytes/ stromal-vascular cells (SVC). Treatments with an agonist of TLR3 were conducted in human adipocyte cultures under normal conditions and upon conditions that simulated the chronic low-grade inflammatory state of obesity.
RESULTS: Surgery stress raised TLR1 and TLR8 in subcutaneous (SAT), and TLR2 in SAT and visceral (VAT) adipose tissue, while decreasing VAT TLR3 and TLR4. MCM led to increased TLR2 and diminished TLR3, TLR4, and TLR5 expressions in human adipocytes. The anti-inflammatory impact of weight loss was concomitant with decreased TLR1, TLR3, and TLR8 in SAT. Cross-sectional associations confirmed increased V/ SAT TLR1 and TLR8, and decreased TLR3 in obese patients, as compared with non-obese subjects. As expected, TLR were predominant in SVC and adipocyte precursor cells, even though expression of all of them but TLR8 (very low levels) was also found in ex vivo isolated and in vitro differentiated adipocytes. Among SVC, CD14+ macrophages showed increased TLR1, TLR2, and TLR7, but decreased TLR3 mRNA. The opposite patterns shown for TLR2 and TLR3 in V/ SAT, SVC, and inflamed adipocytes were observed in blood as well, being TLR3 more likely linked to lymphocyte instead of neutrophil counts. On the other hand, decreased TLR3 in adipocytes challenged with MCM dampened lipogenesis and the inflammatory response to Poly(I:C).
CONCLUSION: Functional variations in the expression of TLR found in blood and hypertrophied fat depots, namely decreased TLR3 in lymphocytes and inflamed adipocytes, are linked to metabolic inflammation.

Keywords: Adipocytes; Adipose tissue; Blood; Gene expression; Humans; Inflammation; Innate immune system; Insulin resistance; Macrophages; Obesity; Toll-like receptors; Type 2 diabetes

DOI: https://doi.org/10.1159/000495487

Front Immunol. 2018 ;9 2564

In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes.

Jacqueline M Ratter, Hanne M M Rooijackers, Guido J Hooiveld, Anneke G M Hijmans, Bastiaan E de Galan, Cees J Tack, Rinke Stienstra.

Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Keywords: cytokines; glycolysis; immunometabolism; innate immune cells; lactate; monocytes

DOI: https://doi.org/10.3389/fimmu.2018.02564

Life Sci. 2018 Nov 22. pii: S0024-3205(18)30746-X. [Epub ahead of print]

Recruited bone marrow derived cells, local stromal cells and IL-17 at the front line of resistance development to anti-VEGF targeted therapies.

Behrad Darvishi, Keivan Majidzadeh-A, Reihane Ghadirian, Marjan Mosayebzadeh, Leila Farahmand.

Although anti-angiogenic agents targeting VEGF have shown affordable beneficial outcomes in several human cancer types, in most pre-clinical and clinical studies, these effects are transient and followed by rapid relapse and tumor regrowth. Recently, it has been suggested that recruited bone marrow derived cells (BMDCs) to the tumor-microenvironment together with stromal cells play an important role in development of resistance to anti-VEGF therapies. Additionally, acquired resistance to anti-VEGF therapies has shown to be mediated partly through overexpression of different pro-angiogenic cytokines and growth factors including G-CSF, IL-6, IL-8, VEGF and FGF by these cells. Alongside, IL-17, a pro-inflammatory cytokine, mostly secreted by infiltrated CD4+ T helper cells, has shown to mediate resistance to anti-VEGF therapies, through recruiting BMDCs and modulating stromal cells activities including endothelial cells, tumor associated macrophages and cancer associated fibroblasts. Here, we examined the role of BMDCs, tumor stromal cells, IL-17 and their negotiation in development of resistance to anti-VEGF targeted therapies.

Keywords: Angiogenesis; Anti-VEGF therapies; Bone marrow derived cells; IL-17; Stromal cells

DOI: https://doi.org/10.1016/j.lfs.2018.11.033