Dataset Information

Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: No association with proinflammatory cytokine production in normoxia.

ABSTRACT: Upon activation with pathogen-associated molecular patterns, metabolism of macrophages and dendritic cells is shifted from oxidative phosphorylation to aerobic glycolysis, which is considered important for proinflammatory cytokine production. Fragments of bacterial peptidoglycan (muramyl peptides) activate innate immune cells through nucleotide-binding oligomerization domain (NOD) 1 and/or NOD2 receptors. Here, we show that NOD1 and NOD2 agonists induce early glycolytic reprogramming of human monocyte-derived macrophages (MDM), which is similar to that induced by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide. This glycolytic reprogramming depends on Akt kinases, independent of mTOR complex 1 and is efficiently inhibited by 2-deoxy-d-glucose (2-DG) or by glucose starvation. 2-DG inhibits proinflammatory cytokine production by MDM and monocyte-derived dendritic cells activated by NOD1 or TLR4 agonists, except for tumor necrosis factor production by MDM, which is inhibited initially, but augmented 4 h after addition of agonists and later. However, 2-DG exerts these effects by inducing unfolded protein response rather than by inhibiting glycolysis. By contrast, glucose starvation does not cause unfolded protein response and, in normoxic conditions, only marginally affects proinflammatory cytokine production triggered through NOD1 or TLR4. In hypoxia mimicked by treating MDM with oligomycin (a mitochondrial ATP synthase inhibitor), both 2-DG and glucose starvation strongly suppress tumor necrosis factor and interleukin-6 production and compromise cell viability. In summary, the requirement of glycolytic reprogramming for proinflammatory cytokine production in normoxia is not obvious, and effects of 2-DG on cytokine responses should be interpreted cautiously. In hypoxia, however, glycolysis becomes critical for cytokine production and cell survival.

SUBMITTER: Murugina NE

PROVIDER: S-EPMC7062164 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: No association with proinflammatory cytokine production in normoxia.

Murugina Nina E NE Budikhina Anna S AS Dagil Yulia A YA Maximchik Polina V PV Balyasova Lyudmila S LS Murugin Vladimir V VV Melnikov Mikhail V MV Sharova Viktoriya S VS Nikolaeva Anna M AM Chkadua Georgy Z GZ Pinegin Boris V BV Pashenkov Mikhail V MV

The Journal of biological chemistry 20200131 10

Upon activation with pathogen-associated molecular patterns, metabolism of macrophages and dendritic cells is shifted from oxidative phosphorylation to aerobic glycolysis, which is considered important for proinflammatory cytokine production. Fragments of bacterial peptidoglycan (muramyl peptides) activate innate immune cells through nucleotide-binding oligomerization domain (NOD) 1 and/or NOD2 receptors. Here, we show that NOD1 and NOD2 agonists induce early glycolytic reprogramming of human mo ...[more]

PMID: 32005665

Similar Datasets

Project description:BackgroundAlpha-momorcharin (α-MMC) is a natural medicine derived from bitter melon and has been found to exert immunomodulatory effects. Our previous study indicated that α-MMC can regulate cytokine release from monocytes, but it remains unknown about its regulatory effect on different types of cytokines, such as inflammatory cytokines or anti-inflammatory cytokines.MethodsLPS-induced M1-type macrophages model and IL-4-induced M2-type macrophages model were established, and the expression of proinflammatory cytokines and anti-inflammatory cytokines were assessed by ELISA after α-MMC was administered. Then, a LPS-induced acute pneumonia mouse model was established, the proinflammatory cytokines levels and inflammatory lesions in lung tissues were examined by ELISA or H&E staining. Furthermore, omics screening analysis and Western blotting verification were performed on TLR4 and JAK1-STAT6 signalling pathway-related proteins to elucidate the regulatory mechanism of α-MMC in those M1 macrophages and M2 macrophages.ResultsAt a noncytotoxic dose of 0.3 μg/mL, α-MMC significantly inhibited the LPS-induced expression of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-8, MIP-1α and MCP-1, by M1 macrophages in a time-dependent manner, but α-MMC did not inhibit the IL-4-induced synthesis of anti-inflammatory cytokines, such as IL-10, IL-1RA, EGF, VEGF, TGF-β and CCL22, by M2 macrophages. Moreover, α-MMC also inhibited inflammatory cytokine expression in an LPS-induced acute pneumonia mouse model and alleviated inflammation in lung tissues. Furthermore, omics screening and Western blotting analysis confirmed that α-MMC inhibited TAK1/p-TAK1 and subsequently blocked the downstream MAPK and NF-κB pathways, thus inhibiting the LPS-induced inflammatory cytokine expression.ConclusionOur results reveal that α-MMC inhibits proinflammatory cytokine expression by M1 macrophages but not anti-inflammatory cytokine expression by M2 macrophages. The efficacy of α-MMC in selectively inhibiting proinflammatory cytokine expression renders it particularly suitable for the treatment of severe inflammation and autoimmune diseases characterized by cytokine storms.

Dataset Information

Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: No association with proinflammatory cytokine production in normoxia.

Publications

Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: No association with proinflammatory cytokine production in normoxia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets