FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4310106442> ?p ?o ?g. }

• W4310106442 endingPage "436" @default.
• W4310106442 startingPage "435" @default.
• W4310106442 abstract "The gut microbiota is a fundamental regulator of host immune responses. Our group previously demonstrated that the depletion of the gut microbiota by broad-spectrum antibiotics (ABX) prevented neutrophil aging (a type of circadian priming) and vaso-occlusion and prolonged survival in a mouse model for sickle cell disease (SCD) (Zhang, D et al. Nature 2015, 570(7570):528-532); the mechanisms involved, however, are as yet unknown. Diverse metabolites are generated by the microbiota from the fermentation of exogenous undigested dietary components and endogenous substrates secreted by the host. Complex carbohydrates are metabolized into short-chain fatty acids (SCFAs), while cholesterol derivatives from the liver are converted into secondary bile acids by intestinal bacteria. The major SCFA producers are Bacteroidetes (gram-negative) and Firmicutes (gram-positive) divisions, and dysbiosis of these bacterial divisions is found in both SCD humans and mice, (Lim, S et al. Am J Hematol 2018, 93(4):E91-E93). Herein, we investigate whether and how microbiota-derived metabolites modulate the dynamics of neutrophils in vaso-occlusive processes in SCD mice. First, to C57BL/6 (wild-type, WT) mice we administered either: 1) one of three main SCFAs, namely sodium butyrate (Na-B), sodium propionate (Na-P), or sodium acetate (Na-A); or 2) a combination of two main secondary bile acids, lithocholic and deoxycholic acids. The number of circulating neutrophils with an aged phenotype (i.e., Ly6Ghi CD11bhi CD62Llo CXCR4pos, Casanova-Acebes, M et al. Cell 2013, 153(5):1025-1035) was assessed by flow cytometry over time. Numbers started to increase at 2h after Na-B administration and we observed a peak of accumulation of total and aged-like neutrophils at 4-5h, with a return to basal after 9h. Consistent with this finding, administration of Na-B to SCD mice led to augmented counts of aged-like neutrophils and impaired survival of mice subjected to inflammation. Interestingly, when SCD mice receiving prolonged ABX treatment (40-45 days) were also given daily Na-B for the last days of ABX treatment, the percentage of aged-like neutrophils in the circulation was higher than that found in the blood of SCD mice under ABX, but without Na-B (55% vs 24%), showing that Na-B by itself is able to reverse the reduction in neutrophil aging promoted by ABX. To address the impact of Na-B in SCD vaso-occlusion, intravital microscopy of the cremaster muscle of SCD mice, after inflammatory stimulus with TNFa, revealed that Na-B abrogated the beneficial effects of ABX and triggered vaso-occlusive processes. We found a 3-fold rise in the adhesion of leukocytes to the endothelium and a 2-fold slower blood flow rate in the microvasculature of mice who received Na-B (see Figure). These results support our hypothesis that the gut microbiota modulates inflammation and vaso-occlusion in SCD through the generation of SCFAs. Because Na-B is known to be a potent inhibitor of histone deacetylase (HDAC) enzymes, we induced HDAC inhibition in WT mice. Vorinostat, a potent synthetic HDAC inhibitor, led to a 3-fold greater expansion of total and aged-like neutrophils in the blood, suggesting a role for HDACs in neutrophil biology. Consistently, in vitro treatment of WT mouse neutrophils with vorinostat or Na-B accelerated the progressive acquisition of an aged-like phenotype, characterized by loss of L-selectin (CD62L). Proteome of neutrophils from WT mice after induction of circadian aging by anti-P and anti-E-selectin antibodies showed that aged neutrophils are similar to neutrophils from vorinostat-treated mice, with down-regulation of genes involved in mRNA processing, protein synthesis, and proteasome complex formation, suggesting that HDAC inhibition is the underlying mechanism driving neutrophil aging. Importantly, the down- and up-regulated pathways found in these neutrophils were the same as those found in SCD mouse neutrophils, and an opposite proteomic profile was observed in neutrophils from ABX-treated SCD mice. Our findings indicate that the intestinal microbiota drives vaso-occlusion and neutrophil aging in SCD mice through the production of metabolites that inhibit HDAC. They also define the microbiota as instigator and innate immunity as effector of vascular disease, such that targeting their crosstalk could be effective at alleviating the devastating symptoms in SCD patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal" @default.
• W4310106442 created "2022-11-30" @default.
• W4310106442 creator A5013509330 @default.
• W4310106442 creator A5021964417 @default.
• W4310106442 creator A5035752030 @default.
• W4310106442 creator A5044390727 @default.
• W4310106442 creator A5060898511 @default.
• W4310106442 creator A5076959286 @default.
• W4310106442 creator A5085568242 @default.
• W4310106442 date "2022-11-15" @default.
• W4310106442 modified "2023-09-28" @default.
• W4310106442 title "Microbial Metabolites Target Histone Deacetylases to Trigger Vascular Inflammation in Sickle Cell Disease" @default.
• W4310106442 doi "https://doi.org/10.1182/blood-2022-169203" @default.
• W4310106442 hasPublicationYear "2022" @default.
• W4310106442 type Work @default.
• W4310106442 citedByCount "0" @default.
• W4310106442 crossrefType "journal-article" @default.
• W4310106442 hasAuthorship W4310106442A5013509330 @default.
• W4310106442 hasAuthorship W4310106442A5021964417 @default.
• W4310106442 hasAuthorship W4310106442A5035752030 @default.
• W4310106442 hasAuthorship W4310106442A5044390727 @default.
• W4310106442 hasAuthorship W4310106442A5060898511 @default.
• W4310106442 hasAuthorship W4310106442A5076959286 @default.
• W4310106442 hasAuthorship W4310106442A5085568242 @default.
• W4310106442 hasBestOaLocation W43101064421 @default.
• W4310106442 hasConcept C142724271 @default.
• W4310106442 hasConcept C1491633281 @default.
• W4310106442 hasConcept C203014093 @default.
• W4310106442 hasConcept C2776914184 @default.
• W4310106442 hasConcept C2779134260 @default.
• W4310106442 hasConcept C502942594 @default.
• W4310106442 hasConcept C54355233 @default.
• W4310106442 hasConcept C552990157 @default.
• W4310106442 hasConcept C64927066 @default.
• W4310106442 hasConcept C71924100 @default.
• W4310106442 hasConcept C86803240 @default.
• W4310106442 hasConceptScore W4310106442C142724271 @default.
• W4310106442 hasConceptScore W4310106442C1491633281 @default.
• W4310106442 hasConceptScore W4310106442C203014093 @default.
• W4310106442 hasConceptScore W4310106442C2776914184 @default.
• W4310106442 hasConceptScore W4310106442C2779134260 @default.
• W4310106442 hasConceptScore W4310106442C502942594 @default.
• W4310106442 hasConceptScore W4310106442C54355233 @default.
• W4310106442 hasConceptScore W4310106442C552990157 @default.
• W4310106442 hasConceptScore W4310106442C64927066 @default.
• W4310106442 hasConceptScore W4310106442C71924100 @default.
• W4310106442 hasConceptScore W4310106442C86803240 @default.
• W4310106442 hasIssue "Supplement 1" @default.
• W4310106442 hasLocation W43101064421 @default.
• W4310106442 hasOpenAccess W4310106442 @default.
• W4310106442 hasPrimaryLocation W43101064421 @default.
• W4310106442 hasRelatedWork W1506160043 @default.
• W4310106442 hasRelatedWork W1569642359 @default.
• W4310106442 hasRelatedWork W1585782290 @default.
• W4310106442 hasRelatedWork W1987822850 @default.
• W4310106442 hasRelatedWork W2437075906 @default.
• W4310106442 hasRelatedWork W2562364476 @default.
• W4310106442 hasRelatedWork W2804986721 @default.
• W4310106442 hasRelatedWork W3198590948 @default.
• W4310106442 hasRelatedWork W4206027097 @default.
• W4310106442 hasRelatedWork W4377016659 @default.
• W4310106442 hasVolume "140" @default.
• W4310106442 isParatext "false" @default.
• W4310106442 isRetracted "false" @default.
• W4310106442 workType "article" @default.