9 results on '"Gaballa JM"'
Search Results
2. Interleukin 21 Drives a Hypermetabolic State and CD4 + T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.
- Author
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Bamidele AO, Mishra SK, Piovezani Ramos G, Hirsova P, Klatt EE, Abdelrahman LM, Sagstetter MR, Davidson HM, Fehrenbach PJ, Valenzuela-Pérez L, Kim Lee HS, Zhang S, Aguirre Lopez A, Kurdi AT, Westphal MS, Gonzalez MM, Gaballa JM, Kosinsky RL, Lee HE, Smyrk TC, Bantug G, Gades NM, and Faubion WA Jr
- Subjects
- Animals, Humans, Mice, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Chronic Disease, Crohn Disease immunology, Crohn Disease metabolism, Crohn Disease pathology, Interleukins metabolism, Interleukins pharmacology, Mice, Inbred C57BL, T-Lymphocytes, Regulatory immunology, Voltage-Dependent Anion Channel 1 metabolism, Voltage-Dependent Anion Channel 1 genetics, Colitis immunology, Colitis metabolism, Colitis pathology, Mitochondria metabolism
- Abstract
Background & Aims: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis., Methods: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4
+ T-cell-induced murine colitis models., Results: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs., Conclusions: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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3. International nomenclature guidelines for the IL-1 family of cytokines and receptors.
- Author
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Gaballa JM, Højen JF, De Graaf DM, Amo-Aparicio J, Marchetti C, Cavalli G, Dinarello A, Li S, Corbisiero MF, Tengesdal IW, Redzic JS, Azam T, Webber WS 3rd, Pankratz KA, May MJ, Cominelli F, Eisenmesser EZ, Kim S, Dinarello CA, and Boraschi D
- Subjects
- Cytokines, Interleukin-1
- Published
- 2024
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4. IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion.
- Author
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Dinarello A, May M, Amo-Aparicio J, Azam T, Gaballa JM, Marchetti C, Tesoriere A, Ghirardo R, Redzic JS, Webber WS 3rd, Atif SM, Li S, Eisenmesser EZ, de Graaf DM, and Dinarello CA
- Subjects
- Animals, Mice, Homeostasis, Intercellular Signaling Peptides and Proteins metabolism, Interleukins metabolism, Organoids metabolism, Stem Cells metabolism, Intestinal Mucosa metabolism, Wnt Signaling Pathway
- Abstract
The IL-1 Family member IL-38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38-deficient mice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5 , Ephb2 , and Olfm4 ) expression compared with wild-type organoids. The IL-38 binding to IL-1R6 and IL-1R9 is still a matter of debate. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9-deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild-type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL-1β have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an antiinflammatory molecule in the SI, maintaining homeostasis.
- Published
- 2023
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5. G9a Modulates Lipid Metabolism in CD4 T Cells to Regulate Intestinal Inflammation.
- Author
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Ramos GP, Bamidele AO, Klatt EE, Sagstetter MR, Kurdi AT, Hamdan FH, Kosinsky RL, Gaballa JM, Nair A, Sun Z, Dasari S, Lanza IR, Rozeveld CN, Schott MB, Urrutia G, Westphal MS, Clarkson BD, Howe CL, Marietta EV, Luckey DH, Murray JA, Gonzalez M, Braga Neto MB, Gibbons HR, Smyrk TC, Johnsen S, Lomberk G, and Faubion WA
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- Mice, Humans, Animals, Lipid Metabolism, T-Lymphocytes, Regulatory metabolism, Chromatin, Inflammation, Cholesterol, Lipids, Forkhead Transcription Factors metabolism, CD4-Positive T-Lymphocytes, Colitis chemically induced, Colitis drug therapy, Colitis genetics
- Abstract
Background & Aims: Although T-cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T-cell differentiation is ill defined, and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored., Methods: Human naive T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) before being characterized via the transcriptome (RNA sequencing), chromatin accessibility (assay for transposase-accessible chromatin by sequencing), protein expression (cytometry by time of flight, flow cytometry), metabolism (mitochondrial stress test, ultrahigh performance liquid chromatography-tandem mas spectroscopy) and function (T-cell suppression assay). The in vivo role of G9a was assessed using 3 murine models., Results: We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3
+ T cells (G9a-inibitors-T regulatory cells [Tregs]) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells, resulting in increased intracellular cholesterol. Metabolomic profiling of G9a-inibitors-Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute trinitrobenzene sulfonic acid-induced colitis secondary to tissue-specific Treg development. Finally, Tregs lacking G9a expression (G9a-knockout Tregs) remain functional chronically and can rescue T-cell transfer-induced colitis., Conclusion: G9a inhibition promotes cholesterol metabolism in T cells, favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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6. BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease.
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Gonzalez MM, Bamidele AO, Svingen PA, Sagstetter MR, Smyrk TC, Gaballa JM, Hamdan FH, Kosinsky RL, Gibbons HR, Sun Z, Ye Z, Nair A, Ramos GP, Braga Neto MB, Wixom AQ, Mathison AJ, Johnsen SA, Urrutia R, and Faubion WA Jr
- Subjects
- Animals, Crohn Disease genetics, Humans, Mice, Mice, Transgenic, Polycomb Repressive Complex 1 genetics, Proto-Oncogene Proteins genetics, T-Lymphocytes, Regulatory pathology, Th1 Cells immunology, Th17 Cells immunology, Crohn Disease immunology, Epigenesis, Genetic immunology, Polycomb Repressive Complex 1 immunology, Proto-Oncogene Proteins immunology, T-Lymphocytes, Regulatory immunology
- Abstract
FOXP3+ Tregs are expanded within the inflamed intestine of human Crohn's disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn's associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine FOXP3+ cells led to systemic inflammation. BMI1-deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant FOXP3+ cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17-like proinflammatory cells, a transition relevant to human Crohn's disease associated CD4+ T cells.
- Published
- 2021
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7. Deregulation of Long Intergenic Non-coding RNAs in CD4+ T Cells of Lamina Propria in Crohn's Disease Through Transcriptome Profiling.
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Braga-Neto MB, Gaballa JM, Bamidele AO, Sarmento OF, Svingen P, Gonzalez M, Ramos GP, Sagstetter MR, Aseem SO, Sun Z, and Faubion WA
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- Aged, Case-Control Studies, Crohn Disease metabolism, Crohn Disease pathology, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Mucous Membrane metabolism, CD4-Positive T-Lymphocytes physiology, Crohn Disease etiology, RNA, Long Noncoding metabolism
- Abstract
Background: The aetiology of Crohn's disease [CD] involves immune dysregulation in a genetically susceptible individual. Genome-wide association studies [GWAS] have identified 200 loci associated with CD, ulcerative colitis, or both, most of which fall within non-coding DNA regions. Long non-coding RNAs [lncRNAs] regulate gene expression by diverse mechanisms and have been associated with disease activity in inflammatory bowel disease. However, disease-associated lncRNAs have not been characterised in pathogenic immune cell populations., Methods: Terminal ileal samples were obtained from 22 CD patients and 13 controls. RNA from lamina propria CD4+ T cells was sequenced and long intergenic non-coding RNAs [lincRNAs] were detected. Overall expression patterns, differential expression [DE], and pathway and gene enrichment analyses were performed. Knockdown of novel lincRNAs XLOC_000261 and XLOC_000014 was performed. Expression of Th1 or Th17-associated transcription factors, T-bet and RORγt, respectively, was assessed by flow cytometry., Results: A total of 6402 lincRNAs were expressed, 960 of which were novel. Unsupervised clustering and principal component analysis showed that the lincRNA expression discriminated patients from controls. A total of 1792 lincRNAs were DE, and 295 [79 novel; 216 known] mapped to 267 of 5727 DE protein-coding genes. The novel lincRNAs were enriched in inflammatory and Notch signalling pathways [p <0.05]. Furthermore, DE lincRNAs in CD patients were more frequently found in DNA regions with known inflammatory bowel disease [IBD]-associated loci. The novel lincRNA XLOC_000261 negatively regulated RORγt expression in Th17 cells., Conclusions: We describe a novel set of DE lincRNAs in CD-associated CD4+ cells and demonstrate that novel lincRNA XLOC_000261 appears to negatively regulate RORγt protein expression in Th17 cells., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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8. Genome Sequences of Cluster K Mycobacteriophages Deby, LaterM, LilPharaoh, Paola, SgtBeansprout, and Sulley.
- Author
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Gaballa JM, Dabrian K, Desai R, Ngo R, Park D, Sakaji E, Sun Y, Tan B, Brinck M, Brobst O, Fernando R, Kim H, McCarthy S, Murphy M, Sarkis A, Sevier P, Singh A, Wu D, Wu MY, Ennis HA, Luhar R, Miller JE, Orchanian SB, Salbato AN, Alam S, Brenner L, Kailani Z, Laskow J, Ma X, Miikeda A, Nol-Bernardino P, Sukhina A, Walas N, Wei W, Do NP, Fournier CT, Kim CJ, Mosier SF, Pierson C, Romero IG, Sanchez M, Sawyerr O, Wang J, Watanabe R, Wu S, Chen A, Kazane K, Kettoola Y, Goodwin EC, Lund AJ, Villella W, Williams D, Freise A, and Moberg Parker J
- Abstract
Mycobacteriophages Deby, LaterM, LilPharaoh, Paola, SgtBeansprout, and Sulley were isolated from soil using Mycobacterium smegmatis mc
2 155. Genomic analysis indicated that they belong to subclusters K1 and K5. Their genomic architectures are typical of cluster K mycobacteriophages, with most variability occurring on the right end of the genome sequence.- Published
- 2019
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9. The Role of Histone Methyltransferases and Long Non-coding RNAs in the Regulation of T Cell Fate Decisions.
- Author
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Gaballa JM, Braga Neto MB, Ramos GP, Bamidele AO, Gonzalez MM, Sagstetter MR, Sarmento OF, and Faubion WA Jr
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- Cell Differentiation immunology, Clinical Trials as Topic, DNA Methylation immunology, Gene Expression Regulation immunology, Genetic Therapy methods, Histone Code, Histones genetics, Histones immunology, Humans, Immune System Diseases immunology, Immune System Diseases surgery, Neoplasms immunology, Neoplasms therapy, Cell Differentiation genetics, Epigenesis, Genetic immunology, Histone Methyltransferases metabolism, RNA, Long Noncoding metabolism, T-Lymphocytes immunology
- Abstract
T cell lineage decisions are critical for the development of proper immune responses to pathogens as well as important for the resolution of inflammatory responses. This differentiation process relies on a combination of intrinsic and extrinsic factors converging upon epigenetic regulation of transcriptional networks relevant to specific T cell lineages. As these biochemical modifications represent therapeutic opportunities in cancer biology and autoimmunity, implications of writers and readers of epigenetic marks to immune cell differentiation and function are highly relevant. Given the ready adoption of histone methyltransferase inhibitors in the clinic, we focus this review on the role of three histone modifying complexes: PRC-1, PRC-2, and G9A in modulating T cell fate decisions. Furthermore, we explore the role of long non-coding RNAs in regulating these processes, and discuss recent advances and challenges of implementing epigenetic therapies into clinical practice.
- Published
- 2018
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