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The Journal of Allergy and Clinical... Jun 2022Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory...
BACKGROUND
Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known.
OBJECTIVE
We sought to decipher macrophage-trained immunity in allergic asthma.
METHODS
We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation in mice, and an in vitro training setup to analyze persistent changes in macrophage eicosanoid, cytokine, and chemokine production as well as the underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or metabolic flux analysis and liquid chromatography-tandem mass spectrometry analysis, respectively.
RESULTS
We found that macrophages differentiated from bone marrow or blood monocyte progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type 2 imprint, which shifted toward a classical inflammatory training over time. HDM-induced allergic airway inflammation elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl peptide receptor 2-TNF-2-HG-PGE/PGE receptor 2 axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice.
CONCLUSION
Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type 2 airway inflammation and thus represents a target for asthma therapy.
Topics: Animals; Asthma; Dermatophagoides pteronyssinus; Disease Models, Animal; Humans; Hypersensitivity; Inflammation; Macrophages; Mice; Prostaglandins E; Pyroglyphidae
PubMed: 34974067
DOI: 10.1016/j.jaci.2021.11.026 -
Antioxidants & Redox Signaling Jun 2015A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both... (Review)
Review
SIGNIFICANCE
A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences.
CRITICAL ISSUES
IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo.
RECENT ADVANCES
The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Aβ1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells.
FUTURE DIRECTIONS
Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.
Topics: Amyloid; Animals; Blood-Brain Barrier; DNA-Binding Proteins; Fatty Acids, Unsaturated; Humans; Inflammation; Mitochondria; Oxidative Stress; Phosphatidylethanolamines; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Protein Binding; Pyrrolidines; Tubulin
PubMed: 25557218
DOI: 10.1089/ars.2014.6154 -
Molecules (Basel, Switzerland) Jun 2011Levuglandins (LGs) and isolevuglandins (isoLGs), formed by rearrangement of endoperoxide intermediates generated through the cyclooxygenase and free radical induced... (Review)
Review
Levuglandins (LGs) and isolevuglandins (isoLGs), formed by rearrangement of endoperoxide intermediates generated through the cyclooxygenase and free radical induced oxidation of polyunsaturated fatty acids (PUFAs), are extraordinarily reactive, forming covalent adducts incorporating protein lysyl ε-amino groups. Because they accumulate, these adducts provide a dosimeter of oxidative injury. This review provides an updated and comprehensive overview of the generation of LG/isoLG in vitro and in vivo and the detection methods for the adducts of LG/isoLG and biological molecules in vivo.
Topics: Animals; Humans; Molecular Structure; Prostaglandins E
PubMed: 21705973
DOI: 10.3390/molecules16075333 -
International Journal of Molecular... May 2023Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF,... (Review)
Review
Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE and PGE. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.
Topics: Animals; Male; Humans; Semen; Arachidonic Acid; Prostaglandins E; Prostaglandins; Fertility
PubMed: 37175913
DOI: 10.3390/ijms24098207 -
British Journal of Clinical Pharmacology Aug 1975
Topics: Aerosols; Animals; Asthma; Bronchi; Bronchodilator Agents; Humans; Indomethacin; Infusions, Parenteral; Isoproterenol; Muscle Tonus; Muscle, Smooth; Prostaglandins; Prostaglandins E; Prostaglandins F
PubMed: 1233987
DOI: 10.1111/j.1365-2125.1975.tb02772.x -
Archives of Disease in Childhood Sep 1981Chronic, non-specific `toddler diarrhoea' in young children is often accompanied by an increase in plasma prostaglandins, particularly PGFα. Although treatment with...
Chronic, non-specific `toddler diarrhoea' in young children is often accompanied by an increase in plasma prostaglandins, particularly PGFα. Although treatment with drugs is generally unnecessary, aspirin is effective in most children with high prostaglandins, and treatment with loperamide is effective in most children with toddler diarrhoea, regardless of the plasma prostaglandin levels. The source of the increased plasma prostaglandins is not known.
Topics: Aspirin; Diarrhea, Infantile; Dinoprostone; Humans; Infant; Loperamide; Prostaglandins E; Prostaglandins F
PubMed: 6945825
DOI: 10.1136/adc.56.9.705 -
Scientific Reports Nov 2022Prostaglandins play a critical role in inflammatory response. To investigate the association of urinary PGE-M, a stable end-product of prostaglandin E2 (PGE) with...
Prostaglandins play a critical role in inflammatory response. To investigate the association of urinary PGE-M, a stable end-product of prostaglandin E2 (PGE) with overall and cause-specific mortality and examine potential effect modifiers, we obtained urinary PGE-M levels of 2927 non-cancerous adults from our previous case-control studies nested in the Shanghai Women's Health Study and Shanghai Men's Health Study, two cohort studies conducted in Shanghai, China. Mortality data and modifiable factors associated with urinary PGE-M were obtained from the parent cohort studies. Using linear regression models, we found that high urinary PGE-M levels were significantly associated with low education, heaving smoking, old age at urine collection, and abdominal obesity. Using Cox proportional hazards models, we found that increase (per standard deviation) of urinary PGE-M levels were significantly associated with overall mortality (adjusted hazard ratio = 1.19, 95% confidence interval: 1.07, 1.33) and particularly deaths from cardiometabolic diseases (adjusted hazard ratio = 1.27, 95% confidence interval: 1.11, 1.44). The increased death risks persisted across different time intervals during the follow-up and were stronger among participants who were younger than 60 (P = 0.0014 for all- cause mortality and P = 0.007 for deaths from cardiometabolic diseases) at urine collection or perhaps among those who had higher education.
Topics: Adult; Male; Humans; Female; Dinoprostone; China; Case-Control Studies; Cohort Studies; Prostaglandins E; Cardiovascular Diseases; Risk Factors
PubMed: 36344823
DOI: 10.1038/s41598-022-23773-x -
Archives of Disease in Childhood Dec 1980Prostaglandins E and F have been shown to be present in breast milk in over 100 times the concentrations found in adult plasma. The ratio of the concentration of the...
Prostaglandins E and F have been shown to be present in breast milk in over 100 times the concentrations found in adult plasma. The ratio of the concentration of the principal circulating metabolite of prostaglandin F (13, 14-dihydro-15-ketoprostaglandin F) to prostaglandin F itself is low (0.3 to 0.5, compared with 15.8 in adult plasma), implying that prostaglandins may have a relatively long half-life in milk. In addition inactive metabolites of thromboxane A2 and prostacyclin are also found in significant amounts. It is speculated that milk prostaglandin play a role in modulating neonatal physiology--for example, gut motility.
Topics: Female; Humans; Milk, Human; Prostaglandins E; Prostaglandins F
PubMed: 7458394
DOI: 10.1136/adc.55.12.950 -
Fertility and Sterility Apr 1987
Topics: Abortion, Induced; Dinoprostone; Female; Humans; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prostaglandins E; Suppositories
PubMed: 3471533
DOI: 10.1016/s0015-0282(16)59134-1 -
The Journal of Cell Biology Nov 1982Free and polymerized tubulin were measured in bone cells and Chinese hamster ovary (CHO) cells cultured on plastic substrata. Polymerized tubulin was stabilized in a...
Free and polymerized tubulin were measured in bone cells and Chinese hamster ovary (CHO) cells cultured on plastic substrata. Polymerized tubulin was stabilized in a microtubule- stabilizing medium (MSM) containing 50 percent glycerol and separated from free tubulin by centrifugation. Tubulin content was assayed in both fractions by the colchicines- binding assay. The measured degree of polymerization in both bone cells and CHO cells varied with stabilixation conditions. The degree of polymerization in both bone cells and CHO cells varied with stabilization conditions. The degree of polymerization in both bone cells and CHO cells varied with stabilization conditions. The degree of polymerization in attached cells was found to increase up to 73 percent during the first 20 min after addition of the MSM at 24 degrees C, and remained constant thereafter. Stabilization of 0 degrees C resulted in a decrease down to 62 percent in the degree of constant thereafter. Stabilization at 0 degrees C resulted in a decrease down to 62 percent in the degree of polymerization during the first 20 min after addition of the MSM at 24 degrees C, and remained constant thereafter. Confluent bone cells maintained at 0 degrees C for 1 h before stabilization contained significantly less polymerized tubulin than control cells kept at 37 degrees C using stabilization both at 0 degrees C and at 24 degrees C. Changes in bone cell morphology induced by incubation of cells with prostaglandin E(1) or E(2), parthyroid hormone, and dibutyryl cyclic AMP were not associated with a change in the degree of tubulin polymerization. This was confirmed morphologically by immunofluorescence using affinity-purified tubulin antibodies: microtubules in hormone- treated cells were not noticeably reorganized when compared to microtubule organization in control cells. They were, however, squeezed closer together in cellular pseudopods due to the altered cell shape. This altered cell shape appears to be correlated with disorganization of the microfilament system, since microfilaments, detected using affinity-purified actin antibodies, did alter drastically their appearance and distribution after hormone addition.
Topics: Alprostadil; Animals; Bone and Bones; Bucladesine; Cell Adhesion; Cell Line; Cells, Cultured; Cold Temperature; Cricetinae; Dinoprostone; Female; Microtubules; Ovary; Parathyroid Hormone; Polymers; Prostaglandins E; Rats; Tubulin
PubMed: 6292234
DOI: 10.1083/jcb.95.2.387