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Effects of inflammatory and anti-inflammatory environments on the macrophage mitochondrial function.

ABSTRACT: Mitochondrial response to inflammation is crucial in the metabolic adaptation to infection. This study aimed to explore the mitochondrial response under inflammatory and anti-inflammatory environments, with a focus on the tricarboxylic acid (TCA) cycle. Expression levels of key TCA cycle enzymes and the autophagy-related protein light chain 3b (LC3b) were determined in raw 264.7 cells treated with lipopolysaccharide (LPS) and metformin (Met). Additionally, reactive oxygen species (ROS) levels and mitochondrial membrane potential were assessed using flow cytometry. Moreover, 8-week-old C57BL/6J mice were intraperitoneally injected with LPS and Met to assess the mitochondrial response in vivo. Upon LPS stimulation, the expression of key TCA enzymes, including citrate synthase, ?-ketoglutarate dehydrogenase, and isocitrate dehydrogenase 2, and the mitochondrial membrane potential decreased, whereas the levels of LC3b and ROS increased. However, treatment with Met inhibited the reduction of LPS-induced enzyme levels as well as the elevation of LC3b and ROS levels. In conclusion, the mitochondrial TCA cycle is affected by the inflammatory environment, and the LPS-induced effects can be reversed by Met treatment.

SUBMITTER: Ji D

PROVIDER: S-EPMC7684315 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Effects of inflammatory and anti-inflammatory environments on the macrophage mitochondrial function.

Ji Dong D Yin Jian-Yun JY Li Dan-Feng DF Zhu Chang-Tai CT Ye Jian-Ping JP Pan Yuan-Qing YQ

Scientific reports 20201123 1

Mitochondrial response to inflammation is crucial in the metabolic adaptation to infection. This study aimed to explore the mitochondrial response under inflammatory and anti-inflammatory environments, with a focus on the tricarboxylic acid (TCA) cycle. Expression levels of key TCA cycle enzymes and the autophagy-related protein light chain 3b (LC3b) were determined in raw 264.7 cells treated with lipopolysaccharide (LPS) and metformin (Met). Additionally, reactive oxygen species (ROS) levels an ...[more]

PMID: 33230189

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Project description:Saccharomyces cerevisiae is a single-celled fungal microorganism. S. cerevisiae-derived vacuoles are closely related to mammalian lysosomes, which play a role in the degradation of macromolecules by various hydrolytic enzymes. This study evaluated the anti-inflammatory efficacy of S. cerevisiae-vacuoles by inhibiting inflammatory mediators induced by lipopolysaccharide (LPS). The results showed that treatment with 5, 10, and 20 µg/mL of S. cerevisiae-derived vacuoles almost completely inhibited the LPS-induced expression of iNOS protein and mRNA. Moreover, vacuoles significantly reduced the mRNA expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) in LPS-stimulated macrophages compared to the control cells. The immunofluorescence analysis confirmed that S. cerevisiae-derived vacuoles inhibited the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated cells. Taken together, the treatment with S. cerevisiae-derived vacuoles alone activated macrophages, but LPS-activated macrophages modulated pro-inflammatory mediators by downregulating the NF-κB pathway. These results suggest that S. cerevisiae-derived vacuoles may have therapeutic potential in the treatment of inflammatory diseases. In conclusion, our study provides new insights into the immunomodulatory effects of S. cerevisiae-derived vacuoles and their potential as a novel anti-inflammatory agent. IMPORTANCE This study investigates the potential of using vacuoles derived from the yeast Saccharomyces cerevisiae as a new anti-inflammatory therapy. Inflammation is a natural response of the immune system to invading pathogens, but when it is dysregulated, it can lead to chronic diseases. The researchers found that treating macrophages with vacuoles significantly reduced the production of pro-inflammatory cytokines and iNOS, markers of inflammation when they were stimulated with lipopolysaccharide. The study also showed that vacuoles inhibited the NF-κB signaling pathway, which is involved in the induction of pro-inflammatory cytokines in macrophages. These findings suggest that S. cerevisiae-derived vacuoles may have potential as a new therapeutic agent for regulating the inflammatory response in various diseases. Further studies are needed to evaluate the efficacy and safety of vacuoles in vivo and to elucidate the underlying mechanisms of their anti-inflammatory effects.

Project description:Aim: The current study aimed to examine the effects of resistance exercise with concomitant consumption of high vs. low daily doses of non-steroidal anti-inflammatory drugs (NSAIDs) on mitochondrial oxidative phosphorylation in skeletal muscle. As a secondary aim, we compared the effects of eccentric overload with conventional training. Methods: Twenty participants were randomized to either a group taking high doses (3 × 400 mg/day) of ibuprofen (IBU; 27 ± 5 year; n = 11) or a group ingesting a low dose (1 × 75 mg/day) of acetylsalicylic acid (ASA; 26 ± 4 year; n = 9) during 8 weeks of supervised knee extensor resistance training. Each of the subject's legs were randomized to complete the training program using either a flywheel (FW) device emphasizing eccentric overload, or a traditional weight stack machine (WS). Maximal mitochondrial oxidative phosphorylation (CI+IIP) from permeabilized skeletal muscle bundles was assessed using high-resolution respirometry. Citrate synthase (CS) activity was assessed using spectrophotometric techniques and mitochondrial protein content using western blotting. Results: After training, CI+IIP decreased (P < 0.05) in both IBU (23%) and ASA (29%) with no difference across medical treatments. Although CI+IIP decreased in both legs, the decrease was greater (interaction p = 0.015) in WS (33%, p = 0.001) compared with FW (19%, p = 0.078). CS activity increased (p = 0.027) with resistance training, with no interactions with medical treatment or training modality. Protein expression of ULK1 increased with training in both groups (p < 0.001). The increase in quadriceps muscle volume was not correlated with changes in CI+IIP (R = 0.16). Conclusion: These results suggest that 8 weeks of resistance training with co-ingestion of anti-inflammatory drugs reduces mitochondrial function but increases mitochondrial content. The observed changes were not affected by higher doses of NSAIDs consumption, suggesting that the resistance training intervention was the prime mediator of the decreased mitochondrial phosphorylation. Finally, we noted that flywheel resistance training, emphasizing eccentric overload, rescued some of the reduction in mitochondrial function seen with conventional resistance training.

Project description:BACKGROUND: Commercial Atlantic salmon is fed diets with high fat levels to promote fast and cost-effective growth. To avoid negative impact of obesity, food additives that stimulate fat metabolism and immune function are of high interest. TTA, tetradecylthioacetic acid, is a synthetic fatty acid that stimulates mitochondrial ?-oxidation most likely by activation of peroxysome proliferator-activated receptors (PPARs). PPARs are important transcription factors regulating multiple functions including fat metabolism and immune responses. Atlantic salmon experiments have shown that TTA supplemented diets significantly reduce mortality during natural outbreaks of viral diseases, suggesting a modulatory role of the immune system. RESULTS: To gain new insights into TTA effects on the Atlantic salmon immune system, a factorial, high-throughput microarray experiment was conducted using a 44K oligo nucleotide salmon microarray SIQ2.0 and the Atlantic salmon macrophage-like cell line ASK. The experiment was used to determine the transcriptional effects of TTA, the effects of TTA in poly(I:C) elicited cells and the effects of pretreating the cells with TTA. The expression patterns revealed that a large proportion of genes regulated by TTA were related to lipid metabolism and increased mitochondrial ?-oxidation. In addition we found that for a subset of genes TTA antagonized the transcriptional effects of poly(I:C). This, together with the results from qRT-PCR showing an increased transcription of anti-inflammatory IL10 by TTA, indicates anti-inflammatory effects. CONCLUSIONS: We demonstrate that TTA has significant effects on macrophage-like salmon cells that are challenged by the artificial dsRNA poly(I:C). The immune stimulatory effect of TTA in macrophages involves increased lipid metabolism and suppressed inflammatory status. Thus, suggesting that TTA directs the macrophage-like cells towards alternative, anti-inflammatory, activation. This has positive implications for TTA as a feed additive.

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Effects of inflammatory and anti-inflammatory environments on the macrophage mitochondrial function.

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Effects of inflammatory and anti-inflammatory environments on the macrophage mitochondrial function.

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