IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages.
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ABSTRACT:
SUBMITTER: Wang X
PROVIDER: S-EPMC7688333 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Metabolic trait in macrophages can be rewired by insulin like growth factor 2 (IGF2), however, how IGF2 modulates the cellular dynamics and functionality remains unclear. We demonstrate here that IGF2 exhibits dual and opposing roles in controlling inflammatory phenotypes in macrophages via regulating glucose metabolism. Such difference relies on the dominant activation of IGF2R by low dose IGF2 and IGF1R by high dose IGF2. IGF2R activation leads to proton rechanneling to the mitochondrial intermembrane space, and enables sustained oxidative phosphorylation. Mechanistically,low dose IGF2 induces nucleus translocation of IGF2R that promotes Dnmt3a-mediated DNA methylation via activating GSK3β, and subsequently impairs the expression ofvacuolar-type H+-ATPase (v-ATPase).This sequestrated assembly of v-ATPase inhibits the channeling of protons to lysosomes and leads to their rechanneling to mitochondria. An IGF2R-specific IGF2 mutant only induces anti-inflammatory response and inhibits colitis progression. Altogether, our findings highlight a novel role of IGF2R activation in dictating anti-inflammatory macrophages.
2020-12-07 | GSE151404 | GEO
Project description:IGF2R-initiated Proton Rechanneling Dictates an Anti-inflammatory Property in Macrophages
| PRJNA635686 | ENA
Project description:BackgroundPeroxiredoxins (Prxs) are proposed to function as damage-associated molecular patterns (DAMPs) and contribute to post-ischemic neuroinflammation and brain injury by activating Toll-like receptor (TLR) 4 at the acute and subacute phases after ischemic stroke. However, there are few studies concerning the inflammatory profiles of six distinct subtypes of Prxs (Prx1-Prx6). Our previous study demonstrated that the protective effect of ligustilide (LIG) against cerebral ischemia was associated with inhibition of neuroinflammatory response and Prx/TLR4 signaling in rats. Herein, the present study explored the inflammatory members of Prxs and the effect of LIG on their inflammatory responses in macrophages.Methodology/principal findingsThe murine RAW264.7 macrophages were treated with each of exogenous recombinant Prxs at a range of 1 to 50 nM for 24 h. The WST-1 test showed that Prx3 exhibited a significant cytotoxicity, whereas the rest five Prxs did not affect cellular viability. The quantitative measurements with spectrometry or ELISA indicated that three subtypes, Prx1, Prx2 and Prx4, increased production of proinflammatory mediators, including nitric oxide (NO) metabolites, tumor necrosis factor-? (TNF-?), and interleukin-6 (IL-6) in a concentration-dependent manner. Immunostaining demonstrated that 20 nM Prx1, Prx2 or Prx4 significantly increased expression of TLR4 and iNOS and nuclear translocation of NF-?B p65. However, Prx5 and Prx6 showed no poinflammatory effect in macrophages. Remarkably, LIG treatment effectively inhibited the inflammatory response induced by Prx1, Prx2 and Prx4.ConclusionThree members of Prxs, Prx1, Prx2 and Prx4, are inflammatory DAMPs that induce TLR4 activation and inflammatory response in macrophages, which is effectively inhibited by LIG. These results suggest that inflammatory Prxs-activated macrophages may provide a novel cellular model for screening the potential inhibitors of DAMPs-associated inflammatory diseases such as stroke. Moreover, selective blocking strategies targeting the inflammatory subtypes of Prxs probably provide promising therapeutic approaches with a prolonged time window for stroke.
| S-EPMC5055302 | biostudies-literature
Project description:Platelet-activating factor receptor (PAFR) is a G protein-coupled receptor (GPCR) implicated in many diseases. Toll-like receptors (TLRs) play a critical role in shaping innate and adaptive immune responses. In this study, we investigated whether PAFR signaling changes the macrophages responsiveness to agonists of TLR2 (Pam3Cys), TLR4 (LPS), and TLR3 agonist Poly(I:C). Exogenous PAF inhibited the production of pro-inflammatory cytokines (IL-12p40, IL-6, and TNF-?) and increased anti-inflammatory IL-10 in macrophages challenged with Pam3Cys and LPS, but not with Poly (I:C). PAF did not affect mRNA expression of MyD88, suggesting that PAF acts downstream the adaptor. PAF inhibited LPS-induced phosphorylation of NF-?B p65 and increased NF-?B p105 phosphorylation, which is processed in the proteasome to generate p50 subunit. The PAF potentiation of IL-10 production was dependent on proteasome processing but independent of NF-?B transactivation domain. Inhibition of p50 abolished the PAF-induced IL-10 production. These findings indicate that the impaired transcriptional activity of the p65 subunit and the enhanced p105 phosphorylation induced by PAF are responsible for down regulation of pro-inflammatory cytokines and up regulation of IL-10, respectively, in LPS-challenged macrophages. Together, our data unveil a heretofore unrecognized role for PAFR in modulating activation of NF-?B in macrophages.
| S-EPMC4995467 | biostudies-literature
Project description:The pathology of skin immune diseases such as atopic dermatitis is closely related to the overproduction of cytokines by macrophages. Although the pathological functions of macrophages in skin are known, mechanisms of how they detect the tissue environment remain unknown. TRPV4, a nonselective cation channel with high Ca2+ permeability, is activated at physiological temperatures from 27 to 35°C and involved in the functional control of macrophages. However, the relationship between TRPV4 function in macrophages and skin immune disease is unclear. In this study, we demonstrate that TRPV4 activation inhibits NF-κB signaling, resulting in the suppression of IL-1β production in both human primary monocytes and macrophages derived from human primary monocytes. A TRPV4 activator also inhibited the differentiation of human primary monocytes into GM-CSF M1 macrophages but not M-CSF M2 macrophages. We also observed a significant increase in the number of inducible NO synthase-positive/TRPV4-negative dermal macrophages in atopic dermatitis compared with healthy human skin specimens. Our findings provide insight into the physiological relevance of TRPV4 to the regulation of macrophages during homeostasis maintenance and raise the potential for TRPV4 to be an anti-inflammatory target.
| S-EPMC10563396 | biostudies-literature
Project description:Macrophages are notable immune cells that are recruited to the injury sites after peripheral nerve injury. Following peripheral nerve injury, increasing numbers of macrophages engulf debris and promote nerve regeneration. However, changes of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, two types of macrophages with dissimilar biological functions, have not been discovered. In the current study, the expression profiles of M1 and M2 macrophage marker genes in the sciatic nerve stumps and dorsal root ganglions (DRGs) after rat sciatic nerve injury were determined using RNA sequencing. Robust up-regulation of macrophage marker genes was observed in the injured sciatic nerve stumps as compared with in the DRGs. Measurement of the dynamic expression levels of M1 macrophage specific marker genes CD38 and Gpr18 as well as M2 macrophage specific marker genes Egr2 and Myc suggested that M1 macrophages were highly involved at all tested time points after peripheral nerve injury while M2 macrophage might be more involved in the later phase after nerve injury. Dynamic changes of M1 macrophage-inducing miRNAs showed that miR-18a, miR-19b, miR-21, miR-29a, and miR-29b were elevated in the injured nerve stump. These up-regulated miRNAs might mediate macrophage polarization by targeting multiple genes, such as Pten. Collectively, our study explored the unique temporal patterns of pro-inflammatory and anti-inflammatory macrophages after peripheral nerve injury for genetic aspects and provided a deeper understanding of the cellular and molecular basis of microenvironment reconstruction after peripheral nerve injury.
| S-EPMC9057386 | biostudies-literature
Project description:Mesenchymal stem cells (MSC) are not universal and may be subject to dynamic changes upon local milieus in vivo and after isolation and cultivation in vitro. Here, we demonstrate that MSC derived from murine pericardial adipose tissue (pMSC) constitute two cohorts of population distinguished by the level of CD73 expression (termed as CD73high and CD73low pMSC). Transplantation of two types of cells into mouse hearts after myocardial infarction (MI) revealed that the CD73high pMSC preferentially brought about structural and functional repair in comparison to the PBS control and CD73low pMSC. Furthermore, the CD73high pMSC displayed a pronounced anti-inflammatory activity by attenuating CCR2+ macrophage infiltration and upregulating several anti-inflammatory genes 5 days after in vivo transplantation and ex vivo cocultivation with peritoneal macrophages. The immunomodulatory effect was not seen in cocultivation experiments with pMSC derived from CD73 knockout mice (CD73-/-) but was partially blocked by pretreatment of the A2b receptor antagonist, PSB603. The results highlight a heterogeneity of the CD73 expression that may be related to its catalytic products on the modulation of the local immune response and thus provide a possible explanation to the inconsistency of the regenerative results when different sources of donor cells were used in stem cell-based therapy.
| S-EPMC6525959 | biostudies-literature
Project description:RationaleThe underlying pathophysiology of bronchopulmonary dysplasia includes a macrophage-mediated host response orchestrated by anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARγ) and anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf2). These have not yet been studied in combination. This study tested the hypothesis that combined inflammatory and oxidative stressors would interact and change PPARγ- and Nrf2-regulated gene expression and antioxidant capacity. Therefore, we investigated the effect of dual stimulation with lipopolysaccharide and hyperoxia in murine bone marrow-derived macrophages (BMDM).MethodsSub-confluent BMDM from wild-type C57BL/6J mice were treated with lipopolysaccharide (LPS) 1ug/mL for 2 hours followed by room air (21% oxygen) or hyperoxia (95% oxygen) for 24 hours. Taqman real time-polymerase chain reaction gene expression assays, total antioxidant capacity assays, and Luminex assays were performed.ResultsSupernatants of cultured BMDM contained significant antioxidant capacity. In room air, LPS treatment decreased expression of PPARγ and Nrf2, and increased expression of tumor necrosis factor-alpha and heme oxygenase-1; similar findings were observed under hyperoxic conditions. LPS treatment decreased cellular total antioxidant capacity in room air but not in hyperoxia. Increased expression of sulfiredoxin-1 in response to hyperoxia was not observed in LPS-treated cells. Dual stimulation with LPS treatment and exposure to hyperoxia did not have synergistic effects on gene expression. Cellular total antioxidant capacity was not changed by hyperoxia exposure.ConclusionsOur hypothesis was supported and we demonstrate an interaction between inflammatory and oxidative stressors in a model system of bronchopulmonary dysplasia pathogenesis. The protective anti-oxidant effect of cell culture media may have protected the cells from the most deleterious effects of hyperoxia.
| S-EPMC5590945 | biostudies-literature
Project description:Myricetin has been reported as a promising chemopreventive compound with multiple biofunctions. To evaluate its influence on gene expressions in genome-wide set and further investigate its anti-inflammatory property, the present study performed Gene Ontology and Ingenuity Pathway Analysis (IPA) to describe the basic gene expression characteristics by myricetin treatment in HepG2 cells, confirmed its multi-biofunction by real-time fluorescent quantitative PCR (RT-qPCR), and further verified its anti-inflammatory property by Western blotting and bio-plex-based cytokines assay. The IPA data showed that 337 gene expressions (48% of the top molecules) are disturbed over 2-fold, and the most possible biofunctions of myricetin are the effect on "cardiovascular disease, metabolic disease, and lipid metabolism," via regulation of 28 molecules with statistic score of 46. RT-qPCR data confirmed the accuracy of microarray data, and cytokines assay results indicated that 6 of the total 27 inflammatory cytokine secretions were significantly inhibited by myricetin pretreatment, including TNF-α, IFN-γ, IL-1α, IL-1β, IL-2, and IL-6. The present study is the first time to elucidate the multi-function of myricetin in genome-wide set by IPA analysis and verify its anti-inflammatory property by proteomics of cytokines assay. Therefore, these results enrich the comprehensive bioactivities of myricetin and reveal that myricetin has powerful anti-inflammatory property, which provides encouragement for in vivo studies to verify its possible health benefits.
| S-EPMC6431437 | biostudies-literature
Project description:Galectin-1 (Gal-1) has immunomodulatory activities in various allergic inflammatory disorders, but its potential anti-inflammatory properties on allergic airway diseases have not been confirmed. We explored the pharmacological effects of Gal-1 on the progression of allergic airway inflammation and investigated the underlying mechanism. Female C57BL/6 mice were sensitized on day 0 and challenged with ovalbumin (OVA) on days 14-17 to establish an allergic airway inflammation model. In the challenge phase, a subset of mice was treated intraperitoneally with recombinant Gal-1 (rGal-1) or dexamethasone (Dex). We found that rGal-1 inhibited pulmonary inflammatory cell recruitment, mucus secretion, bronchoalveolar lavage fluid (BALF) inflammatory cell infiltration, and cytokine production. The treatment also suppressed the infiltration of eosinophils into the allergic lung as indicated by decreased expression levels of eotaxin and eosinophil peroxidase (EPX). However, only the expression levels of IL-25, neither IL-33 nor TSLP, were significantly decreased in the lung by rGal-1 treatment. These immunomodulatory effects in the allergic lung were correlated with the activation of extracellular signal-regulated kinase (ERK) signaling pathway and downregulation of endogenous Gal-1. In addition, rGal-1 reduced the plasma concentrations of anti-OVA immunoglobulin E (IgE) and IL-17. Our findings suggest that rGal-1 is an effective therapy for allergic airway inflammation in a murine model and may be a potential pharmacological target for allergic airway inflammatory diseases.
| S-EPMC6535876 | biostudies-literature