scholarly journals Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

2019 ◽  
Author(s):  
Shay Hantisteanu ◽  
Joseph Dicken ◽  
Varda Negreanu ◽  
Dalia Goldenberg ◽  
Ori Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
Early Onset ◽  
Target Genes ◽  
Critical Role ◽  
Substantial Reduction ◽  
Cell Types ◽  
Mononuclear Phagocytes ◽  
Inflammatory Genes ◽  
A Genome ◽  
Anti Inflammatory

ABSTRACTRUNX3 is one of three mammalian Runt-domain transcription factors (TFs) that regulate gene expression in several types of immune cells. Runx3-deficiency in mice is associated with a multitude of defects in the adaptive and innate immunity systems, including the development of early onset colitis. Our study reveals that conditional deletion of Runx3 specifically in mononuclear phagocytes (MNP) (MNPRunx3−/−) but not in T cells, recapitulates the early onset spontaneous colitis seen in Runx3−/− mice.We show that Runx3 is expressed in colonic MNP, including resident macrophages (RM) and the dendritic cell cDC2 subsets and its loss results in impaired differentiation/maturation of both cell types. At the transcriptome level, loss of Runx3 in RM and cDC2 was associated with upregulation of pro-inflammatory genes similar to those in the early onset IBD murine model of RMIl10r−/−. The impaired RM maturation in the absence of Runx3 was associated with a marked decrease in expression of anti-inflammatory and TGFβ-regulated genes. Similarly, the decreased expression of β-catenin signaling associated genes in Runx3-deficient cDC2 indicates their impaired differentiation/maturation. Analysis of ChIP-seq data suggests that in both MNP cell types a significant fraction of these differentially expressed genes are high confidence Runx3 directly regulated genes. Interestingly, several of these putative Runx3 target genes harbor SNPs associated with IBD susceptibility in humans. Remarkably, the impaired maturation and pro-inflammatory phenotype of MNP lacking Runx3 was associated with a substantial reduction in the prevalence of colonic lamina propria Foxp3+ regulatory T cells and an increase in IFNγ-producing CD4+ T cells, underscoring Runx3 critical role in establishing tolerogenic MNP.Together, these data emphasize the dual role of Runx3 in colonic MNP, as a transcriptional repressor of pro-inflammatory genes and an activator of maturation-associated genes including anti-inflammatory genes. Our study highlights the significance of the current MNPRunx3−/− model for understanding of human MNP-associated colitis. It provides new insights into the crucial involvement of Runx3 in intestinal immune tolerance by regulating colonic MNP maturation through TGFβR signaling and anti-inflammatory functions by Il10R signaling, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans including gastrointestinal tract diseases such as celiac and Crohn’s disease.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals TFAM-deficient mouse skin fibroblasts: an ex vivo model of mitochondrial dysfunction

2021 ◽  
Author(s):  
Manuel J. Del Rey ◽  
Carolina Meroño ◽  
Cristina Municio ◽  
Alicia Usategui ◽  
María Mittelbrunn ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Ex Vivo ◽  
Stress Test ◽  
Critical Role ◽  
Substantial Reduction ◽  
Mouse Skin ◽  
Cell Types ◽  
Ex Vivo Model ◽  
Primary Mouse ◽  
Inflammatory Phenotype

Mitochondrial dysfunction in different cell types is associated to several pathological processes and potentially contributes to chronic inflammatory and ageing-related diseases. Mitochondrial Transcription Factor A (TFAM) plays a critical role in maintaining mtDNA integrity and function. Taking advantage of the Tfamfl/fl UBC-Cre/ERT2+/+ mice, we sought to develop a cellular in vitro system to investigate the role of mitochondrial dysfunction in the stromal cell component. We describe an inducible model of mitochondrial dysfunction by stable depletion of TFAM in primary mouse skin fibroblast (SK-FB) after 4-hydroxytamoxifen (4-OHT) administration. Tfam gene deletion caused a sustained reduction of Tfam and mtDNA-encoded mRNA expression in Cre(+) cultured for low (LP) and high passages (HP). Ultimately, Tfam knockout translated into a loss of TFAM protein. TFAM depletion led to a substantial reduction of the mitochondrial respiratory chain (MRC) complexes that was exacerbated in HP SK-FB cultures. The assembly pattern showed that the respiratory complexes fail to reach the respirasome in 4-OHT Cre(+) SK-FB. Functionally, we determined the mitochondrial function and the glycolytic activity by mito-stress and glycolysis-stress test respectively. These analysis showed that mitochondrial dysfunction was developed after long-term 4-OHT treatment in HP Cre(+) SK-FB and was compensated by an increase in the glycolytic capacity. Finally, expression analysis revealed that 4-OHT-treated HP Cre(+) SK-FB showed a senescent and pro-inflammatory phenotype. In conclusion, we have generated and validated the first ex vivo model of fibroblast mitochondrial dysfunction that results in a pro-inflammatory phenotype applicable to explore this process in other cell types in a variety of pathological conditions.

scholarly journals Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Hiroyuki Hosokawa ◽  
Maile Romero-Wolf ◽  
Qi Yang ◽  
Yasutaka Motomura ◽  
Ditsa Levanon ◽  
...  
Keyword(s):  
T Cells ◽  
Target Genes ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Type ◽  
Distal Enhancer ◽  
Distinct Cell Type ◽  
Cell Type Specific ◽  
Group 2

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2, preventing pro-T cells from adopting innate-like fates. In contrast, ILC2s co-express both Bcl11b and Id2. To address this contradiction, we have directly compared Bcl11b action mechanisms in pro-T cells and ILC2s. We found that Bcl11b binding to regions across the genome shows distinct cell type–specific motif preferences. Bcl11b occupies functionally different sites in lineage-specific patterns and controls totally different sets of target genes in these cell types. In addition, Bcl11b bears cell type–specific post-translational modifications and organizes different cell type–specific protein complexes. However, both cell types use the same distal enhancer region to control timing of Bcl11b activation. Therefore, although pro-T cells and ILC2s both need Bcl11b for optimal development and function, Bcl11b works substantially differently in these two cell types.

Abstract 444: Probiotic Administration Mitigates the Detrimental Effects of Myocardial Infarction in Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
John Konhilas
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cardiac Injury ◽  
Cost Effective ◽  
Specific Strain ◽  
Anti Inflammatory ◽  
Microbial Environment

Advances in sequencing and bioinformatics technologies have allowed unprecedented characterization of the gut microbiome. As a result, there is a growing appreciation that our microbial environment plays a critical role in the maintenance of health and the pathogenesis of disease. Accordingly, recent evidence suggests a role for gut microbiota in modulating cardiovascular disease and cardiac injury. We hypothesized that administration of the probiotic, Bifidobacterium animalis subsp. lactis 420 (B420), to mice will mitigate the pathological impact of ischemic heart disease (IHD), and that anti-inflammatory T regulatory (T reg ) immune cells are necessary to impart protection against IHD as a result of B420 administration. Pretreatment with B420 for 14 or 35 days attenuated cardiac injury from ischemia/reperfusion or permanent coronary ligation. Infarcted hearts from B420 treated animals displayed a significant reduction in pro-inflammatory markers and an increase in anti-inflammatory regulatory T cells (T reg ). We further show that T reg immune cells are necessary players to communicate this protection by B420 administration. This protection is due, at least in part, to an increase in anti-inflammatory M2 type macrophages in B420 treated animals. These results suggest that administration of the probiotic B420 protects against cardiac injury and that regulatory T cells mediate this effect. Modulation of the inflammatory response by administration of a specific strain of probiotic may offer a rational, safe, and cost effective way to prevent inflammatory damage after cardiac injury.

Organization and Regulation of the Human Genome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-16-SCI-16
Author(s):  
Bing Ren
Keyword(s):  
Gene Regulation ◽  
Long Range ◽  
Genome Organization ◽  
Mammalian Cells ◽  
Target Genes ◽  
Critical Role ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Organization ◽  
Specific Gene

Abstract The 3-dimensional (3D) chromatin organization plays a critical role in gene regulation. Great strides have been made recently to characterize and identify cis regulatory elements from epigenome profiles in different cell types and tissues, but efforts have just begun to functionally characterize these long-range control elements. Mapping interactions between enhancers and promoters, and understanding how the 3D landscape of the genome constrains such interactions is fundamental to our understanding of genome function. I will present recent findings related to 3D genome organization in mammalian cells, with a particular focus on how chromatin organization contributes to transcriptional regulation. I will describe higher-order organizational features that are observed at the level of both the whole chromosome and individual loci. I will highlight changes in genome organization that occur during the course of differentiation, and discuss the functional relationship between chromatin architecture and gene regulation. Taken together, mounting evidence now shows that the genome organization plays an essential role in orchestrating the lineage-specific gene expression programs through modulating long- range interactions between enhancers and target genes. Disclosures Ren: Arima Genomics, Inc.: Equity Ownership, Patents & Royalties; Eli Lilly: Employment.

scholarly journals Induction of Human Liver X Receptor α Gene Expression Via an Autoregulatory Loop Mechanism

2002 ◽  
Vol 16 (3) ◽  
pp. 506-514 ◽  
Author(s):  
Yu Li ◽  
Charles Bolten ◽  
B. Ganesh Bhat ◽  
Jessica Woodring-Dietz ◽  
Suzhen Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Regulatory Element ◽  
Critical Role ◽  
Cell Types ◽  
Plasma Lipoproteins ◽  
Type I ◽  
Type Ii ◽  
Downstream Target ◽  
X Receptors

Abstract The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRα (hLXRα) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2–4 h. Analysis of the hLXRα promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRα:RXR and LXRβ:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRα:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRα and LXRβ activity, whereas the type II LXRE acts as a weaker and selective mediator of LXRα activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRα gene expression. This would lead to increased hLXRα levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.

scholarly journals Innate Immune Surveillance of Spontaneous B Cell Lymphomas by Natural Killer Cells and γδ T Cells

2004 ◽  
Vol 199 (6) ◽  
pp. 879-884 ◽  
Author(s):  
Shayna E.A. Street ◽  
Yoshihiro Hayakawa ◽  
Yifan Zhan ◽  
Andrew M. Lew ◽  
Duncan MacGregor ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Critical Role ◽  
Immune Surveillance ◽  
Γδ T Cells ◽  
Cell Types ◽  
Tumor Formation ◽  
Innate Immune ◽  
Tumor Rejection ◽  
B Cell Lymphomas

Few studies have demonstrated that innate lymphocytes play a major role in preventing spontaneous tumor formation. We evaluated the development of spontaneous tumors in mice lacking β-2 microglobulin (β2m; and thus MHC class I, CD1d, and CD16) and/or perforin, since these tumor cells would be expected to activate innate effector cells. Approximately half the cohort of perforin gene-targeted mice succumbed to spontaneous disseminated B cell lymphomas and in mice that also lacked β2m, the lymphomas developed earlier (by more than 100 d) and with greater incidence (84%). B cell lymphomas from perforin/β2m gene-targeted mice effectively primed cell-mediated cytotoxicity and perforin, but not IFN-γ, IL-12, or IL-18, was absolutely essential for tumor rejection. Activated NK1.1+ and γδTCR+ T cells were abundant at the tumor site, and transplanted tumors were strongly rejected by either, or both, of these cell types. Blockade of a number of different known costimulatory pathways failed to prevent tumor rejection. These results reflect a critical role for NK cells and γδTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition.

A genome-wide microarray analysis reveals anti-inflammatory target genes of paeonol in macrophages

2008 ◽  
Vol 57 (4) ◽  
pp. 189-198 ◽  
Author(s):  
H. Huang ◽  
E. J. Chang ◽  
Y. Lee ◽  
J. S. Kim ◽  
S. S. Kang ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Target Genes ◽  
Genome Wide ◽  
A Genome ◽  
Anti Inflammatory

scholarly journals Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk.

2021 ◽  
Author(s):  
Eric D Thomas ◽  
Andrew E Timms ◽  
Sarah Giles ◽  
Sarah Harkins-Perry ◽  
Pin Lyu ◽  
...  
Keyword(s):  
Target Genes ◽  
Disease Risk ◽  
Critical Role ◽  
Cell Types ◽  
Regulatory Elements ◽  
Human Retina ◽  
Disease States ◽  
Cell Class ◽  
Single Nucleus ◽  
Highly Correlated

Cis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease.

Abstract 565: Nuclear Receptor NR4A1 Represses SDF1a expression in macrophages and Reduces Atherosclerosis.

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Anouk A Hamers
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Nuclear Receptor ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Muscle Cells ◽  
Wild Type ◽  
Anti Inflammatory

Rationale NR4A1 is a nuclear receptor, also known as Nur77 and is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. NR4A1-knockout (NR4A1 -/- ) mice lack Ly6C - monocytes, but have normal LyC6 + numbers. Macrophages play a critical role in atherosclerosis and we have demonstrated that NR4A1 has an anti-inflammatory function in THP-1 macrophages. The aim of the current study is to assess the function of this receptor in myeloid cells in atherosclerosis. Objective This study aims to delineate the function of Nuclear Receptor NR4A1 in macrophages in atherosclerosis. Methods and results Bone marrow-derived macrophages (BMM) from wild-type and NR4A1 -/- mice were cultured and classically activated with LPS or alternatively activated with IL4. NR4A1 -/- BMM exhibit changed expression of M2-specific markers and a pro-inflammatory polarization in response to LPS with enhanced expression of IL12, IFNγ, and SDF1α. Nitric oxide synthesis is also strongly induced in (non)-stimulated NR4A1 -/- BMM. SDF1α is a potent chemotactic factor for B cells and monocytes. The chemoattractive activity of NR4A1 -/- BMM is abolished by SDF1α inhibiting antibodies as well as by overexpression of NR4A1 in the NR4A1-deficient cells. Luciferase experiments show that NR4A1 binds directly to several response elements present in the mouse and human SDF1α promoter. A ChIP assay confirms these results. The effect of bone marrow-specific NR4A1-deficiency on atherosclerosis was studied in low density lipoprotein receptor-deficient (Ldlr -/- ) mice. Ldlr -/- mice with a NR4A1 -/- bone marrow develop 2.1-fold larger lesions than wild type bone marrow transplanted mice; containing more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF1α expression is also higher in these lesions, which may explain the observed aggravation of lesion formation, since SDF1α is not only a chemoattractant for monocytes but also enhances smooth muscle cell proliferation. Conclusion In macrophages the nuclear receptor NR4A1 has an anti-inflammatory function, represses SDF1α expression and, most importantly, bone-marrow transplantation studies in Ldlr -/- mice revealed that NR4A1 inhibits atherosclerosis.

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