Novel Role for Macrophage Galactose-type Lectin-1 to Regulate Innate Immunity against Mycobacterium tuberculosis
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PROVIDER: PRJNA707548 | ENA |
REPOSITORIES: ENA
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Project description:Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis (Mtb) is characterized by inflammatory pathology and poorly understood mechanisms of innate immunity. Pattern recognition receptors (PRR), expressed on the surface of macrophages, determine the balance of inflammatory and antimicrobial functions that influence disease outcome. Carbohydrate moieties displayed by mycobacteria can serve as PRR ligands for some members of the C-type lectin receptor (CLR) family; interactions that mediate a variety of incompletely understood immune outcomes. This work identifies a novel role for the CLR Macrophage Galactose-type Lectin-1 (MGL-1) in a mouse model of experimental tuberculosis. Murine macrophages upregulated MGL-1 following in vitro exposure to Mtb, while MGL+ cells accumulated at sites of mycobacteria-driven inflammation in the lung. Pulmonary macrophages from MGL-1-deficient mice displayed increased production of pro-inflammatory cytokines (IL-1b, IL-6 and IFN-g) that was associated with greater lipid accumulation, following Mtb infection. Surprisingly for a CLR, we also observed MGL-1-dependent anti-mycobacterial activity as evidenced by greater Mtb proliferation in BMDM, and the lung, of MGL-1 deficient mice. These results identify MGL-1 signaling as an important mechanism that regulates innate immunity against Mtb and indicate potential for the MGL pathway as a novel therapeutic target for anti-TB immunity.
2021-04-30 | GSE168486 | GEO
Project description: Not available
| S-EPMC8702441 | biostudies-literature
Project description:Background The Ca2+-dependent C-type lectin receptor Macrophage Galactose-type Lectin (MGL) is highly expressed by tolerogenic dendritic cells (DC) and macrophages. MGL exhibits a high binding specificity for terminal alpha- and beta-linked GalNAc residues found in Tn, sTn and LacdiNAc antigens. These glycan epitopes are often overexpressed in colorectal cancer (CRC), and, as such, MGL can be used to discriminate tumor from the corresponding healthy tissues. Moreover, the high expression of MGL ligands is associated with poor disease-free survival in stage III of CRC tumors. Nonetheless, the glycoproteins expressed by tumor cells that are recognized by MGL have hitherto remained elusive. Methods Using a panel of three CRC cell lines (HCT116, HT29 and LS174T), recapitulating CRC diversity, we performed FACS staining and pull-down assays using a recombinant soluble form of MGL (and a mutant MGL as control) combined with mass spectrometry-based (glyco)proteomics. Results HCT116 and HT29, but not LS174T, are high MGL-binding CRC cell lines. On these cells, the major cell surface binding proteins are receptors (e.g. MET, PTK7, SORL1, PTPRF) and integrins (ITGB1, ITGA3). From these proteins, several N- and/or O-glycopeptides were identified, of which some carried either a LacdiNAc or Tn epitope.
2020-01-09 | PXD016726 | Pride
Project description:Monocyte differentiation into macrophages represents one of the cornerstone processes in innate host defense. In addition, immunological imprinting of either tolerance or trained immunity after an initial infection determines the functional fate of innate immune cells and the susceptibility of the host to secondary infections. Here we comprehensively characterize the epigenetic profiles of these functional states relative to healthy adult naM-CM-/ve monocytes. Inflammatory and metabolic pathways are strongly modulated in the derived macrophages, including decreased activation of inflammasome components. The cAMP-dependent signaling pathway is remodeled and adrenergic signaling was functionally implicated in trained innate immunity induction in vivo. Interestingly, M-oM-^AM-"-Glucan trains innate immune cells through extensive remodeling of distal regulatory region-bound histone acetylation, resulting in a sizeable exclusive epigenomic signature. Accordingly, genome-wide transcription factor footprint analysis reveals a specific transcription factor repertoire at trained cell-specific enhancers when recouped with epigenetic data, forming a rich hypothesis generator to manipulate innate immunity. Monocytes were pre-incubated either with cell culture medium (RPMI), M-NM-2-glucan (5M-BM-5g/mL) or with LPS (100ng/mL), for 24 hours in a total volume of 10 mL. After a wash-out, cells were cultured in RPMI supplemented with 10% human pool serum. Monocytes were collected at different time points (0 h and 6 d after treatment) and counted before further treatment for chromatin immunoprecipitation, RNA or DNaseI treatment. Different donor Buffycoats (BC) were used as independent replicates. Replicates were generated for all the profiles including ChIPseq,RNAseq and DNaseIseq.
2014-09-26 | E-GEOD-58310 | biostudies-arrayexpress
Project description:Mechanisms through which the microbiome communicates with the systemic immune system remain unclear. We have identified a family of microbiome Bacteroidota-derived lipopeptides – the serine-glycine (S/G) lipids, and specifically L654 – that are TLR2 ligands, access the systemic circulation, and potentially link the microbiome and systemic innate immunity. We have previously postulated that L654 and the S/G lipids regulate systemic innate immunity by entering the systemic circulation and mediating weak TLR2 interactions that maintain “normal” levels of innate immune signaling feedback inhibitors. In proof-of-concept studies, we reported that increasing systemic L654 levels in mice by administering exogenous L654 intravenously significantly diminishes systemic innate immune responses and attenuates murine autoimmunity. In the present study, our goal was to confirm the role of the microbiome in mediating this mode of immunoregulation by decreasing the microbiome-based production of S/G lipids. We now report that decreasing microbiome Bacteroidota in mice using a specific oral antibiotic/rest protocol reduces fecal and plasma S/G lipids levels and significantly enhances systemic innate immune responses. Replenishing systemic levels of S/G lipids after antibiotic treatment through exogenous administration of L654 returns innate immune responses to normal levels, confirming the regulatory role of S/G lipids in this mode of microbiome regulation. Finally, RNAseq analysis of splenic monocytes derived from antibiotic-treated and control mice with or without exogenous L654 prior to ex vivo stimulation demonstrates that the antibiotic/rest protocol and the concomitant decrease in microbiome S/G lipids and Bacteroidota has significant downregulatory effects on normal homeostatic pro-inflammatory pathways. These effects are also associated with downregulation of specific proinflammatory pathway inhibitors, which may suggest a potential mechanism underlying the enhancement in ex vivo innate immune stimulated responses of these monocytes. Overall, our results suggest that S/G lipids are microbiome-derived bacterial factors capable of regulating systemic innate immunity and as such are manipulatable targets with therapeutic potential for enhancing or decreasing innate immunity in the context of infectious, malignant, and autoimmune diseases.
2024-06-20 | GSE269771 | GEO
Project description:Mechanisms through which the microbiome communicates with the systemic immune system remain unclear. We have identified a family of microbiome Bacteroidota-derived lipopeptides – the serine-glycine (S/G) lipids, and specifically L654 – that are TLR2 ligands, access the systemic circulation, and potentially link the microbiome and systemic innate immunity. We have previously postulated that L654 and the S/G lipids regulate systemic innate immunity by entering the systemic circulation and mediating weak TLR2 interactions that maintain “normal” levels of innate immune signaling feedback inhibitors. In proof-of-concept studies, we reported that increasing systemic L654 levels in mice by administering exogenous L654 intravenously significantly diminishes systemic innate immune responses and attenuates murine autoimmunity. In the present study, our goal was to confirm the role of the microbiome in mediating this mode of immunoregulation by decreasing the microbiome-based production of S/G lipids. We now report that decreasing microbiome Bacteroidota in mice using a specific oral antibiotic/rest protocol reduces fecal and plasma S/G lipids levels and significantly enhances systemic innate immune responses. Replenishing systemic levels of S/G lipids after antibiotic treatment through exogenous administration of L654 returns innate immune responses to normal levels, confirming the regulatory role of S/G lipids in this mode of microbiome regulation. Finally, RNAseq analysis of splenic monocytes derived from antibiotic-treated and control mice prior to ex vivo stimulation demonstrates that the antibiotic/rest protocol and the concomitant decrease in microbiome S/G lipids and Bacteroidota has significant downregulatory effects on normal homeostatic pro-inflammatory pathways. These effects are also associated with downregulation of specific proinflammatory pathway inhibitors, which may suggest a potential mechanism underlying the enhancement in ex vivo innate immune stimulated responses of these monocytes. Overall, our results suggest that S/G lipids are microbiome-derived bacterial factors capable of regulating systemic innate immunity and as such are manipulatable targets with therapeutic potential for enhancing or decreasing innate immunity in the context of infectious, malignant, and autoimmune diseases.
2024-06-12 | GSE236817 | GEO
Project description:Transcriptional landscape of MyceliopTranscriptional profiling of Myceliophthora thermophila on galactose and metabolic engineering for improved galactose utilization thora thermophila responding to soluble starch and the role of regulator AmyR on polysaccharide degradation Efficient biological conversion of all sugars from lignocellulosic biomass is necessary for cost-effective production of biofuels and commodity chemicals. Galactose is the next most abundant sugar in many hemicelluloses and it will be important to capture this carbon for an efficient bioconversion process of plant biomass. Thermophilic fugus Myceliophthora thermophila has been used as cell factory to produce biochemicals directly from renewable polysaccharides. This study determined the transcriptomic profiles of M. thermophila responding to galactose and identified the gene involved in the oxido-reductive pathway for galactose degradation, of which hexokinase might be the rate-limiting enzyme in this thermophilic fungus. Galactokinase was necessary for high induction of galactose transporter and disruption of galK resulted in decreased galactose utilization. Both of galactokinase deletion and sugar transporter overexpression could further activate the oxido-reductive pathway and led to improved galactose utilization. In addition, disruption of the Leloir pathway brought about reduced tolerance to cell wall perturbation, oxidative stress and high osmolality. In order to accelerate galactose consumption, the third galactose-degradation pathway- De Ley-Doudoroff pathway was successfully integrated into M. thermophila and the consumption rate of galactose was increased by 57%. This study will be benefit for the rational design of fungal strains to produce biofuels and biochemical from plant biomass, especially, marine plant biomass with the abundant of galactose, such as red seaweed and molasses.
2021-02-05 | GSE165516 | GEO
Project description: Not available
| S-EPMC1450005 | biostudies-literature
Project description:B cell linker protein (BLNK) is a pivotal adaptor protein that interfaces the B cell receptor (BCR)-associated spleen tyrosine kinase (Syk) to regulate B cell function and development. However, it is still not well understood whether BLNK is involved in Syk-coupled C-type lectin receptor (CLR) signaling in myeloid cells, particularly in the context of antifungal immunity. Here, we show that stimulation with fungi-derived β-glucans or α-mannans induced the phosphorylation of BLNK in macrophages, which was significantly impaired due to the deficiency of CLRs including Dectin-1 and Dectin-2, as well as their downstream mediators Syk and Fc-receptor gamma-chain (FcRγ). Furthermore, BLNK is induced to be interacted with casitas B-lineage lymphoma (c-Cbl), which is completely dependent on the engagement of Dectin-1 and Dectin-2. Notably, BLNK deficiency facilitates CLR-mediated recruitment of c-Cbl/phosphatidylinositol 3-kinase (PI3K) complex to F-actin cytoskeleton, thereby promoting macrophage migration. Consequently, mice with monocyte-specific deficiency of BLNK are highly resistant to the infection with Candida albicans, a major human fungal pathogen, through increasing the infiltration of Ly6C+macrophages into kidneys. Together, our data indicate that BLNK functions downstream of Syk-coupled CLRs to negatively regulate antifungal immunity against C. albicans infection. These findings unravel a previously unidentified role of BLNK that negatively regulates macrophage migration through inhibiting CLR-mediated recruitment of c-Cbl/PI3K complex to the cytoskeleton.
2023-11-07 | GSE246891 | GEO
Project description: Not available
| S-EPMC54736 | biostudies-other