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1.
Nat Immunol ; 17(6): 677-86, 2016 06.
Article in English | MEDLINE | ID: mdl-27089382

ABSTRACT

Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promoted autophagy flux through derepression of key autophagy effectors (such as ATG5, ATG12, LC3B and LAMP1) and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which enhanced lipid catabolism and Mtb xenophagy. These data define a mammalian miRNA circuit used by Mtb to coordinately inhibit autophagy and reprogram host lipid metabolism to enable intracellular survival and persistence in the host.


Subject(s)
Autophagy/genetics , Lipid Metabolism/genetics , Lysosomes/physiology , Macrophages/physiology , MicroRNAs/metabolism , Mycobacterium tuberculosis/physiology , Tuberculosis/genetics , Animals , Cells, Cultured , Host-Pathogen Interactions , Humans , Immune Evasion , Lysosomes/microbiology , Macrophages/microbiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , Signal Transduction , Transcription Factors/metabolism
2.
Nat Immunol ; 14(8): 812-20, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23812099

ABSTRACT

Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1ß (IL-1ß) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-ß and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1ß production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1ß and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.


Subject(s)
Alzheimer Disease/immunology , Atherosclerosis/immunology , CD36 Antigens/immunology , Carrier Proteins/immunology , Diabetes Mellitus, Type 2/immunology , Inflammation/immunology , Animals , CD36 Antigens/genetics , Carrier Proteins/genetics , Inflammasomes/immunology , Interleukin-1beta/immunology , Lipoproteins, LDL/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Microscopy, Fluorescence , NLR Family, Pyrin Domain-Containing 3 Protein , RNA/chemistry , RNA/genetics , Real-Time Polymerase Chain Reaction
3.
Immunity ; 44(2): 368-79, 2016 Feb 16.
Article in English | MEDLINE | ID: mdl-26885859

ABSTRACT

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.


Subject(s)
Interferon-gamma/metabolism , Macrophages/physiology , Membrane Glycoproteins/metabolism , Mycobacterium tuberculosis/immunology , Receptors, Interleukin-1/metabolism , Tuberculosis, Pulmonary/immunology , Animals , Autophagy/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , HEK293 Cells , Humans , Immunity, Innate/genetics , MAP Kinase Signaling System/genetics , Macrophages/microbiology , Membrane Glycoproteins/genetics , Mice , Mice, Knockout , Polymorphism, Genetic , Protein Binding/genetics , RNA, Small Interfering/genetics , Receptors, Interferon/metabolism , Receptors, Interleukin-1/genetics , Tuberculosis, Pulmonary/genetics , Interferon gamma Receptor
4.
Trends Immunol ; 42(10): 846-848, 2021 10.
Article in English | MEDLINE | ID: mdl-34538594

ABSTRACT

Selectively targeting facets of neutrophil function could benefit infectious and inflammatory diseases. Amara et al. report on a compound which blocks human neutrophil activation by activating the glycolytic enzyme phosphofructokinase, liver-type (PFKL). Altering glucose fate by modulating this key enzymatic step could dramatically alter the function and fate of phagocytes.


Subject(s)
Neutrophils , Phagocytes , Glucose , Humans , Neutrophil Activation , Phosphofructokinase-1
5.
Nat Immunol ; 11(2): 141-7, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19946272

ABSTRACT

The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.


Subject(s)
Apoptosis Regulatory Proteins/immunology , Gene Expression Regulation/immunology , MicroRNAs/immunology , RNA-Binding Proteins/immunology , Signal Transduction/immunology , Toll-Like Receptor 4/immunology , Animals , Apoptosis Regulatory Proteins/metabolism , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Humans , Immunoprecipitation , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-6/immunology , Interleukin-6/metabolism , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Mice , MicroRNAs/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism , Polymerase Chain Reaction , RNA-Binding Proteins/metabolism , Receptors, Interleukin-1/immunology , Receptors, Interleukin-1/metabolism , Toll-Like Receptor 4/metabolism , Transfection
6.
Immunology ; 162(2): 145-159, 2021 02.
Article in English | MEDLINE | ID: mdl-33020911

ABSTRACT

In the face of ineffective vaccines, increasing antibiotic resistance and the decline in new antibacterial drugs in the pipeline, tuberculosis (TB) still remains pandemic. Exposure to Mycobacterium tuberculosis (Mtb), which causes TB, results in either direct elimination of the pathogen, most likely by the innate immune system, or infection and containment that requires both innate and adaptive immunity to form the granuloma. Host defence strategies against infectious diseases are comprised of both host resistance, which is the ability of the host to prevent invasion or to eliminate the pathogen, and disease tolerance, which is defined by limiting the collateral tissue damage. In this review, we aim to examine the metabolic demands of the immune cells involved in both host resistance and disease tolerance, chiefly the macrophage and T-lymphocyte. We will further discuss how baseline metabolic heterogeneity and inflammation-driven metabolic reprogramming during infection are linked to their key immune functions containing mycobacterial growth and instructing protective immunity. Targeting key players in immune cellular metabolism may provide a novel opportunity for treatments at different stages of TB disease.


Subject(s)
Host-Pathogen Interactions/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Adaptive Immunity/immunology , Animals , Humans , Immune Tolerance/immunology , Immunity, Innate/immunology , Inflammation/immunology , Inflammation/microbiology , Macrophages/immunology , Macrophages/microbiology , Tuberculosis/microbiology
7.
Br J Nutr ; 125(6): 628-632, 2021 03 28.
Article in English | MEDLINE | ID: mdl-32892755

ABSTRACT

As COVID-19 continues to spread worldwide, severe disease and mortality have been observed in obese patients. We discuss how obesity and obesity-associated factors such as 'meta-flammation', dietary fat intake and paradoxical suppression of the innate immune response within the pulmonary compartment may be crucial determinants in the host response to a novel viral pathogen. Modulation of immune cell bioenergetics and metabolic potential plays a central role in the innate immune response to infection, and as we strive to combat this new global health threat, immunometabolism of the innate immune system warrants attention.


Subject(s)
COVID-19/immunology , Immune System/virology , Obesity/immunology , Obesity/virology , SARS-CoV-2/immunology , COVID-19/mortality , Dietary Fats/immunology , Eating/immunology , Energy Metabolism/immunology , Humans , Immunity, Innate/immunology , Inflammation , Obesity/mortality , Respiratory System/immunology , Respiratory System/virology
8.
J Allergy Clin Immunol ; 146(4): 706-720, 2020 10.
Article in English | MEDLINE | ID: mdl-32841652

ABSTRACT

Metabolic inflammation (metaflammation) is characteristic of obesity-related metabolic disorders, associated with increased risk of development of type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), or cardiovascular disease. Metaflammation refers to a chronic, low-grade systemic inflammation as opposed to the classical transient and acute inflammatory responses of the innate immune system. Metaflammation is driven by a range of adverse dietary factors, including saturated fatty acids and some sugars, suggesting that certain dietary triggers may be particularly relevant beyond simple excessive dietary intake presenting as obesity. Importantly, obese patients with diabetes have a higher risk of infection and display gut microbiota profiles characteristic of dysfunctional immunity. Targeting metaflammation has also emerged as a strategy to attenuate metabolic disease. In this review we explore how different nutrition interventions may reconfigure disrupted metabolic inflammation in type 2 diabetes and nonalcoholic fatty liver disease by reestablishing a conventional proinflammatory program in innate immune cells and/or correcting dysbiosis to dampen systemic inflammation. We begin by reviewing concepts of metabolic inflammation relating to IL-1ß inflammation and how it is induced by dietary and/or metabolic stressors. We then explore whether and how dietary interventions may attenuate processes pertaining to metaflammation, either directly or indirectly via the microbiome. Hence, we hope to bring new perspectives to alleviate the metaflammation typifying metabolic disease.


Subject(s)
Disease Susceptibility , Energy Metabolism , Inflammation/etiology , Inflammation/metabolism , Obesity/complications , Obesity/metabolism , Cardiovascular Diseases/etiology , Diabetes Mellitus, Type 2/etiology , Diet , Humans , Inflammation/diagnosis , Non-alcoholic Fatty Liver Disease/etiology , Nutritional Status , Toll-Like Receptors/metabolism
10.
Semin Immunol ; 28(5): 450-468, 2016 10.
Article in English | MEDLINE | ID: mdl-27780657

ABSTRACT

Successful immune responses to pathogens rely on efficient host innate processes to contain and limit bacterial growth, induce inflammatory response and promote antigen presentation for the development of adaptive immunity. This energy intensive process is regulated through multiple mechanisms including receptor-mediated signaling, control of phago-lysomal fusion events and promotion of bactericidal activities. Inherent macrophage activities therefore are dynamic and are modulated by signals and changes in the environment during infection. So too does the way these cells obtain their energy to adapt to altered homeostasis. It has emerged recently that the pathways employed by immune cells to derive energy from available or preferred nutrients underline the dynamic changes associated with immune activation. In particular, key breakpoints have been identified in the metabolism of glucose and lipids which direct not just how cells derive energy in the form of ATP, but also cellular phenotype and activation status. Much of this comes about through altered flux and accumulation of intermediate metabolites. How these changes in metabolism directly impact on the key processes required for anti-microbial immunity however, is less obvious. Here, we examine the 2 key nutrient utilization pathways employed by innate cells to fuel central energy metabolism and examine how these are altered in response to activation during infection, emphasising how certain metabolic switches or 'reprogramming' impacts anti-microbial processes. By examining carbohydrate and lipid pathways and how the flux of key intermediates intersects with innate immune signaling and the induction of bactericidal activities, we hope to illustrate the importance of these metabolic switches for protective immunity and provide a potential mechanism for how altered metabolic conditions in humans such as diabetes and hyperlipidemia alter the host response to infection.


Subject(s)
Energy Metabolism , Host-Pathogen Interactions , Immunity , Inflammation/etiology , Inflammation/metabolism , Animals , Drug Discovery , Energy Metabolism/drug effects , Glucose/metabolism , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immune System/cytology , Immune System/immunology , Immune System/metabolism , Immunity/drug effects , Immunomodulation , Inflammation/drug therapy , Lipid Metabolism , Metabolic Networks and Pathways
11.
Am J Respir Cell Mol Biol ; 59(5): 572-579, 2018 11.
Article in English | MEDLINE | ID: mdl-29944387

ABSTRACT

Smoking is a major risk factor driving the tuberculosis epidemic, and smokers' alveolar macrophages (AM) demonstrate significant immune defects after infection. Recently, macrophage glycolytic reprogramming has emerged as crucial in the early host immune response to Mycobacterium tuberculosis (Mtb) infection. In the present study, we sought to compare baseline metabolic characteristics and the glycolytic response to infection of human AM from smokers and nonsmokers. AM were obtained at bronchoscopy, and extracellular flux analyses were performed to determine baseline metabolic characteristics compared with human monocyte-derived macrophages (MDM). Metabolic characterization of AM from smokers and nonsmokers was performed similarly. After infection with Mtb, differences in glycolytic response were measured by extracellular flux analyses and gene expression analyses and correlated with production of glycolysis-driven IL-1ß and prostaglandin E2. Similar experiments were performed in cigarette smoke extract-treated MDM as an alternative model. At baseline, human AM from nonsmokers have a significantly lower extracellular acidification rate/oxygen consumption rate ratio than MDM (P < 0.05), but they retain substantial glycolytic reserve. Compared with nonsmokers' AM, smokers' AM demonstrate reduced metabolic activity, reduced glycolytic reserve (P = 0.051), and reduced spare respiratory capacity (P < 0.01). After infection with Mtb, smokers' AM have significantly reduced glycolytic response, as measured by extracellular flux analyses (P < 0.05) and glycolytic gene expression analyses. Cigarette smoke extract-treated MDM similarly demonstrate reduced metabolic activity and reserves, as well as impaired glycolytic response to infection. Human AM demonstrate metabolic plasticity that allows glycolytic reprogramming to occur after Mtb infection. In smokers, this metabolic reserve is significantly attenuated, with consequent impairment of the glycolytic response to infection.


Subject(s)
Cigarette Smoking/adverse effects , Energy Metabolism/immunology , Macrophages, Alveolar/immunology , Metabolome , Mycobacterium tuberculosis/immunology , Pulmonary Alveoli/immunology , Tuberculosis/immunology , Cells, Cultured , Energy Metabolism/drug effects , Glycolysis , Humans , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/microbiology , Mycobacterium tuberculosis/drug effects , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/microbiology , Respiratory Function Tests , Tuberculosis/microbiology , Tuberculosis/pathology
12.
J Immunol ; 196(6): 2444-9, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26873991

ABSTRACT

Recent advances in immunometabolism link metabolic changes in stimulated macrophages to production of IL-1ß, a crucial cytokine in the innate immune response to Mycobacterium tuberculosis. To investigate this pathway in the host response to M. tuberculosis, we performed metabolic and functional studies on human alveolar macrophages, human monocyte-derived macrophages, and murine bone marrow-derived macrophages following infection with the bacillus in vitro. M. tuberculosis infection induced a shift from oxidative phosphorylation to aerobic glycolysis in macrophages. Inhibition of this shift resulted in decreased levels of proinflammatory IL-1ß and decreased transcription of PTGS2, increased levels of anti-inflammatory IL-10, and increased intracellular bacillary survival. Blockade or absence of IL-1R negated the impact of aerobic glycolysis on intracellular bacillary survival, demonstrating that infection-induced glycolysis limits M. tuberculosis survival in macrophages through induction of IL-1ß. Drugs that manipulate host metabolism may be exploited as adjuvants for future therapeutic and vaccination strategies.


Subject(s)
Immunity, Innate/immunology , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/microbiology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/metabolism , Animals , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Glycolysis/immunology , Humans , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Macrophages, Alveolar/immunology , Mice , Mice, Inbred C57BL , Mycobacterium tuberculosis/immunology , Real-Time Polymerase Chain Reaction , Tuberculosis, Pulmonary/microbiology
13.
Nature ; 478(7369): 404-7, 2011 Oct 19.
Article in English | MEDLINE | ID: mdl-22012398

ABSTRACT

Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.


Subject(s)
Chlorocebus aethiops , Gene Expression Regulation/drug effects , Lipoproteins, HDL/blood , Lipoproteins, VLDL/blood , Liver/drug effects , MicroRNAs/antagonists & inhibitors , Oligoribonucleotides, Antisense/pharmacology , Triglycerides/blood , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Cells, Cultured , Chlorocebus aethiops/blood , Chlorocebus aethiops/genetics , Chlorocebus aethiops/metabolism , Cholesterol, LDL/blood , Gene Silencing , HEK293 Cells , Humans , Liver/metabolism , Male , MicroRNAs/metabolism , Time Factors
14.
Front Nutr ; 11: 1346706, 2024.
Article in English | MEDLINE | ID: mdl-38425482

ABSTRACT

Introduction: Macrofungi, such as edible mushrooms, have been used as a valuable medical resource for millennia as a result of their antibacterial and immuno-modulatory components. Mushrooms contain dietary fibers known as ß-glucans, a class of polysaccharides previously linked to the induction of Trained Immunity. However, little is known about the ability of mushroom-derived ß-glucans to induce Trained Immunity. Methods & results: Using various powdered forms of the white button mushroom (Agaricus bisporus), we found that mouse macrophages pre-treated with whole mushroom powder (WMP) displayed enhanced responses to restimulation with TLR ligands, being particularly sensitive to Toll-like receptor (TLR)-2 stimulation using synthetic lipopeptides. This trained response was modest compared to training observed with yeast-derived ß-glucans and correlated with the amount of available ß-glucans in the WMP. Enriching for ß-glucans content using either a simulated in-vitro digestion or chemical fractionation retained and boosted the trained response with WMP, respectively. Importantly, both WMP and digested-WMP preparations retained ß-glucans as identified by nuclear magnetic resonance analysis and both displayed the capacity to train human monocytes and enhanced responses to restimulation. To determine if dietary incorporation of mushroom products can lead to Trained Immunity in myeloid cells in vivo, mice were given a regimen of WMP by oral gavage prior to sacrifice. Flow cytometric analysis of bone-marrow progenitors indicated alterations in hematopoietic stem and progenitor cells population dynamics, with shift toward myeloid-committed multi-potent progenitor cells. Mature bone marrow-derived macrophages derived from these mice displayed enhanced responses to restimulation, again particularly sensitive to TLR2. Discussion: Taken together, these data demonstrate that ß-glucans from common macrofungi can train innate immune cells and could point to novel ways of delivering bio-available ß-glucans for education of the innate immune system.

15.
Am J Clin Nutr ; 120(1): 257-268, 2024 07.
Article in English | MEDLINE | ID: mdl-38705359

ABSTRACT

The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases. Novel advances in our understanding of immunometabolic processes may critically lead to interventions to reduce disease severity and progression. An important example in this regard relates to obesity, which has a multifaceted effect on immunity, activating the proinflammatory pathways such as the inflammasome and disrupting cellular homeostasis. This multifaceted effect of obesity can be investigated through study of downstream conditions using cellular and systemic investigative techniques. To further explore this field, the National Institutes of Health P30 Nutrition Obesity Research Center at Harvard, in partnership with Harvard Medical School, assembled experts to present at its 24th Annual Symposium entitled "Adiposity, Immunity, and Inflammation: Interrelationships in Health and Disease" on 7 June, 2023. This manuscript seeks to synthesize and present key findings from the symposium, highlighting new research and novel disease-specific advances in the field. Better understanding the interaction between metabolism and immunity offers promising preventative and treatment therapies for obesity-related immunometabolic diseases.


Subject(s)
Adiposity , Inflammation , Obesity , Humans , Inflammation/immunology , Obesity/immunology , Adipose Tissue/metabolism , Adipose Tissue/immunology , Immunity
16.
iScience ; 27(3): 109030, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38361630

ABSTRACT

Fungal ß-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in ß-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse ß-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages in vitro and mice bone marrow in vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming, and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of ß-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.

17.
Mol Nutr Food Res ; 67(14): e2200845, 2023 07.
Article in English | MEDLINE | ID: mdl-37195234

ABSTRACT

SCOPE: Mushrooms are valued as an edible and medical resource for millennia. As macrofungi, they possess conserved molecular components recognized by innate immune cells like macrophages, yet unlike pathogenic fungi, they do not trigger the immune system in the same way. That these well-tolerated foods both avoid immuno-surveillance and have positive health benefits, highlights the dearth of information on the interactions of mushroom-derived products with the immune system. METHODS AND RESULTS: Using powders produced from the common white button mushroom, Agaricus bisporus, it is observed that pre-treatment of mouse and human macrophages with mushroom powders attenuates innate immune signaling triggered by microbial ligands like LPS and  ß-glucans, including NFκB activation and pro-inflammatory cytokine production. This effect of mushroom powders is observed at lower doses of TLR ligands, suggesting a model of competitive inhibition whereby mushroom compounds bind and occupy innate immune receptors, precluding activation by microbial stimuli. This effect is preserved following simulated digestion of the powders. Moreover, in vivo delivery of mushroom powders attenuates the development of colitis in a DSS-mouse model. CONCLUSION: This data highlights an important anti-inflammatory role for powdered A. bisporus mushrooms, which can be further utilized to develop complementary approaches to modulate chronic inflammation and disease.


Subject(s)
Agaricus , Humans , Ligands , Powders , Immunity, Innate
18.
J Biol Chem ; 286(29): 25531-9, 2011 Jul 22.
Article in English | MEDLINE | ID: mdl-21628465

ABSTRACT

Toll-like receptors (TLRs) modulate the expression of multiple microRNAs (miRNAs). Here, we report the down-regulation of miR-107 by TLR4 in multiple cell types. The miR-107 sequence occurs in an intron within the sequence encoding the gene for pantothenate kinase 1α (PanK1α), which is regulated by the transcription factor peroxisome proliferator-activating receptor α (PPAR-α). PanK1α is also decreased in response to lipopolysaccharide (LPS). The effect on both miR-107 and PanK1α is consistent with a decrease in PPAR-α expression. We have found that the putative miR-107 target cyclin-dependent kinase 6 (CDK6) expression is increased by TLR4 as a result of the decrease in miR-107. This effect is required for increased adhesion of macrophages in response to LPS, and CDK6-deficient mice are resistant to the lethal effect of LPS. We have therefore identified a mechanism for LPS signaling which involves a decrease in miR-107 leading to an increase in CDK6.


Subject(s)
Cyclin-Dependent Kinase 6/metabolism , Down-Regulation , Macrophages/cytology , Macrophages/metabolism , MicroRNAs/genetics , Toll-Like Receptor 4/metabolism , Animals , Cell Adhesion/drug effects , Cyclin-Dependent Kinase 6/genetics , DEAD-box RNA Helicases/metabolism , Down-Regulation/drug effects , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Mice , MicroRNAs/metabolism , Myeloid Differentiation Factor 88/metabolism , PPAR alpha/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Ribonuclease III/metabolism , Time Factors , Transcription Factor RelA/metabolism , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/metabolism
20.
Front Endocrinol (Lausanne) ; 13: 919223, 2022.
Article in English | MEDLINE | ID: mdl-35957811

ABSTRACT

Patients with type-2 diabetes (T2D) are more likely to develop severe respiratory tract infections. Such susceptibility has gained increasing attention since the global spread of Coronavirus Disease 2019 (COVID-19) in early 2020. The earliest reports marked T2D as an important risk-factor for severe forms of disease and mortality across all adult age groups. Several mechanisms have been proposed for this increased susceptibility, including pre-existing immune dysfunction, a lack of metabolic flexibility due to insulin resistance, inadequate dietary quality or adverse interactions with antidiabetic treatments or common comorbidities. Some mechanisms that predispose patients with T2D to severe COVID-19 may indeed be shared with other previously characterized respiratory tract infections. Accordingly, in this review, we give an overview of response to Influenza A virus and to Mycobacterium tuberculosis (Mtb) infections. Similar risk factors and mechanisms are discussed between the two conditions and in the case of COVID-19. Lastly, we address emerging approaches to address research needs in infection and metabolic disease, and perspectives with regards to deployment or repositioning of metabolically active therapeutics.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Influenza, Human , Respiratory Tract Infections , Tuberculosis , COVID-19/complications , Diabetes Mellitus, Type 2/complications , Humans , Influenza, Human/complications , Influenza, Human/epidemiology , SARS-CoV-2
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