scholarly journals PARG Suppresses Tumorigenesis and Downregulates Genes Controlling Angiogenesis, Inflammatory Response, and Immune Cell Recruitment

2022 ◽  
Author(s):  
Sarah Johnson ◽  
Yaroslava Karpova ◽  
Danping Guo ◽  
Atreyi Ghatak ◽  
Dmitriy A. Markov ◽  
...  
Keyword(s):  
Immune Cell ◽  
Critical Role ◽  
Tumor Growth Inhibition ◽  
Rna Seq ◽  
Cell Recruitment ◽  
Tumor Onset ◽  
Tumor Tissues ◽  
Immune Cell Recruitment

Abstract Chemokines are highly expressed in tumor microenvironment and play a critical role in all aspects of tumorigenesis, including the recruitment of tumor-promoting immune cells, activation of cancer-associated fibroblasts, angiogenesis, metastasis, and growth. Poly(ADP-ribose) polymerase (PARP) is a multi-target transcription regulator with high levels of poly(ADP-ribose) (pADPr) being reported in a variety of cancers. Furthermore, poly(ADP-ribose) glycohydrolase (PARG), an enzyme that degrades pADPr, has been reported to be downregulated in tumor tissues with abnormally high levels of pADPr. In conjunction to this, we have recently reported that the reduction of pADPr, by either pharmacological inhibition of PARP or PARG’s overexpression, disrupts renal carcinoma cell malignancy in vitro. Here, we use 3T3 mouse embryonic fibroblasts, a universal model for malignant transformation, to follow the effect of PARG upregulation on cells’ tumorigenicity in vivo. We found that the overexpression of PARG in mouse allografts produces significantly smaller tumors with a delay in tumor onset. As downregulation of PARG has also been implicated in promoting the activation of pro-inflammatory genes, we also followed the gene expression profile of PARG-overexpressing 3T3 cells using RNA-seq approach and observed that chemokine transcripts are significantly reduced in those cells. Our data suggest that the upregulation of PARG may be potentially useful for the tumor growth inhibition in cancer treatment and as anti-inflammatory intervention.

scholarly journals Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model

2020 ◽  
Vol 34 ◽  
pp. 205873842097489
Author(s):  
Jiang Wang ◽  
Bo Wang ◽  
Xin Lv ◽  
Yingjie Wang
Keyword(s):  
Alveolar Bone ◽  
Immune Cell ◽  
Critical Role ◽  
Therapeutic Drug ◽  
Mice Model ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Tnf Α

Periodontitis is an inflammatory disease caused by host immune response, resulting in a loss of periodontium and alveolar bone. Immune cells, such as T cells and macrophages, play a critical role in the periodontitis onset. Halofuginone, a natural quinazolinone alkaloid, has been shown to possess anti-fibrosis, anti-cancer, and immunomodulatory properties. However, the effect of halofuginone on periodontitis has never been reported. In this study, a ligature-induced mice model of periodontitis was applied to investigate the potential beneficial effect of halofuginone on periodontitis. We demonstrated that the administration of halofuginone significantly reduced the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in vivo, and markedly suppressed immune cell infiltration into the infected sites. Furthermore, we also observed that halofuginone treatment blocked the T-helper 17 (Th17) cell differentiation in vivo and in vitro. We demonstrated for the first time that halofuginone alleviated the onset of periodontitis through reducing immune responses.

Ip-10 plays a critical role in Th1-mediated colitis: Its role in immune cell recruitment to the Mln and colon

2003 ◽  
Vol 124 (4) ◽  
pp. A151
Author(s):  
Jae Geun Hyun ◽  
Zheng Zhang ◽  
Andrew Luster ◽  
Joel Weinstock ◽  
Daniel Berg ◽  
...  
Keyword(s):  
Immune Cell ◽  
Critical Role ◽  
Cell Recruitment ◽  
Immune Cell Recruitment

scholarly journals Senescent Thyrocytes, Similarly to Thyroid Tumor Cells, Elicit M2-like Macrophage Polarization In Vivo

Biology ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 985
Author(s):  
Mara Mazzoni ◽  
Giuseppe Mauro ◽  
Lucia Minoli ◽  
Loredana Cleris ◽  
Maria Chiara Anania ◽  
...  
Keyword(s):  
Cell Lines ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Thyroid Tumor ◽  
Thyroid Cells ◽  
Immunodeficient Mice ◽  
Tumor Onset ◽  
Tumor Stages

Inflammation plays a critical role in thyroid cancer onset and progression. We previously characterized the in vitro interplay between macrophages and senescent human thyrocytes and thyroid tumor-derived cell lines, modeling the early and the late thyroid tumor phases, respectively. We reported that both models are able to induce pro-tumoral M2-like macrophage polarization, through the activation of the COX2-PGE2 axis. Here, we investigated the presence of macrophage infiltrating cells in mouse xenografts derived from the above described cells models. We showed that subcutaneous injection in immunodeficient mice of both senescent human thyrocytes and thyroid tumor-derived cell lines elicits macrophage recruitment. Furthermore, considering the type of macrophage infiltrate, we observed a stronger infiltration of Arginase I positive cells (M2-like). Overall, these results demonstrate the in vivo capability of senescent and tumor thyroid cells to recruit and polarize macrophages, suggesting that the promotion of a pro-tumoral microenvironment through tumor associated macrophages may occurs in late as well as in early thyroid tumor stages, favoring tumor onset and progression.

A reconfigurable microscale assay enables insights into cancer-associated fibroblast modulation of immune cell recruitment

2021 ◽  
Vol 13 (4) ◽  
pp. 87-97
Author(s):  
Jiaquan Yu ◽  
Amber Piazza ◽  
Sidney Sparks ◽  
Laurel E Hind ◽  
David J Niles ◽  
...  
Keyword(s):  
Immune Cell ◽  
Neutrophil Infiltration ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Neoplastic Tissue ◽  
Cell Recruitment ◽  
Cancer Associated Fibroblast ◽  
First Time ◽  
Immune Cell Recruitment

Abstract Innate immune cell infiltration into neoplastic tissue is the first line of defense against cancer and can play a deterministic role in tumor progression. Here, we describe a series of assays, using a reconfigurable microscale assay platform (i.e. Stacks), which allows the study of immune cell infiltration in vitro with spatiotemporal manipulations. We assembled Stacks assays to investigate tumor–monocyte interactions, re-education of activated macrophages, and neutrophil infiltration. For the first time in vitro, the Stacks infiltration assays reveal that primary tumor-associated fibroblasts from specific patients differ from that associated with the benign region of the prostate in their ability to limit neutrophil infiltration as well as facilitate monocyte adhesion and anti-inflammatory monocyte polarization. These results show that fibroblasts play a regulatory role in immune cell infiltration and that Stacks has the potential to predict individual patients’ cancer-immune response.

scholarly journals Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) is Required for Immune Priming of the Endothelium in Atherogenic Disturbed Flow Conditions

2021 ◽  
Author(s):  
Jessica A Hensel ◽  
Sarah-Anne E Nicholas ◽  
Evan R Jellison ◽  
Amy L Kimble ◽  
Antoine Menoret ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Innate Immune ◽  
Polypyrimidine Tract ◽  
Cell Recruitment ◽  
Polypyrimidine Tract Binding ◽  
Polypyrimidine Tract Binding Protein ◽  
Immune Cell Recruitment

NFkB mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through upregulation of adhesion molecules Icam1 and Vcam. The endothelium is primed for cytokine activation of NFkB by exposure to low and disturbed blood flow (LDF) in vivo and by LDF or static conditions in cultured cells. While priming leads to an exaggerated expression of Icam1 and Vcam following cytokine stimulation, the molecular underpinnings are not fully understood. We showed that alternative splicing of genes regulating NFkB signaling occurs during priming, but the functional implications of this are not known. We hypothesize that the regulation of splicing by RNA-binding splice factors is critical for priming. Here, we perform a CRISPR screen in cultured aortic endothelial cells to determine whether splice factors active in the response to LDF participate in endothelial cell priming. Using Icam1 and Vcam induction by TNFalpha stimulation as a marker of priming, we identify polypyrimidine tract binding protein (Ptbp1) as a required splice factor. Ptbp1 expression is increased and its motifs are enriched nearby alternatively spliced exons in endothelial cells exposed to LDF in vivo in a platelet dependent manner, indicating its induction by early innate immune cell recruitment. At a mechanistic level, deletion of Ptbp1 inhibited NFkB nuclear translocation and transcriptional activation. These changes coincided with altered splicing of key components of the NFkB signaling pathway that were similarly altered in the LDF response. However, these splicing and transcriptional changes could be restored by expression of human PTBP1 cDNA in Ptbp1 deleted cells. In vivo, endothelial specific deletion of Ptbp1 reduced myeloid cell infiltration at regions of LDF in atherosclerotic mice. In human coronary arteries, PTBP1 expression correlates with expression of TNF pathway genes and amount of plaque. Together, our data suggest that Ptbp1, which is activated in the endothelium by innate immune cell recruitment in regions of LDF, is required for priming of the endothelium for subsequent NFkB activation and myeloid cell recruitment in vascular inflammation.

scholarly journals Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

2019 ◽  
Author(s):  
Federica De Leo ◽  
Giacomo Quilici ◽  
Mario Tirone ◽  
Valeria Mannella ◽  
Francesco De Marchis ◽  
...  
Keyword(s):  
Rational Design ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Cell Recruitment ◽  
Redox States ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractExtracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.

scholarly journals Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection

2017 ◽  
Vol 9 (5) ◽  
pp. 437-440 ◽  
Author(s):  
Viviane Labrie ◽  
Patrik Brundin
Keyword(s):  
Immune Cell ◽  
Point Mutations ◽  
Alpha Synuclein ◽  
Cell Recruitment ◽  
Normal Functions ◽  
Intestinal Infections ◽  
Increased Risk ◽  
Or Gene ◽  
Immune Cell Recruitment

Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood. We discuss a recent study reporting that viral infection induces alpha-synuclein expression in neurons of the gastrointestinal tract. Alpha-synuclein levels increased during norovirus infection in the duodenum of children. In an in vitro paradigm, monomeric and oligomeric alpha-synuclein acted as chemoattractants for neutrophils and monocytes, and promoted the maturation of dendritic cells. This suggests that alpha-synuclein facilitates immune responses to infection. We explore the possibility that intestinal infections, and associated inflammation, place individuals at increased risk of PD by increasing alpha-synuclein levels and promoting the formation of alpha-synuclein aggregates that propagate in a prion-like fashion via the vagal nerve to the brainstem.

scholarly journals ASC-Mediated Inflammation and Pyroptosis Attenuates Brucella abortus Pathogenesis Following the Recognition of gDNA

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1008
Author(s):  
Juselyn D. Tupik ◽  
Sheryl L. Coutermarsh-Ott ◽  
Angela H. Benton ◽  
Kellie A. King ◽  
Hanna D. Kiryluk ◽  
...  
Keyword(s):  
Brucella Abortus ◽  
Immune Cell ◽  
Intracellular Localization ◽  
Protective Role ◽  
In Vivo Studies ◽  
Inflammasome Activation ◽  
Cell Recruitment ◽  
Molecular Patterns ◽  
Immune Cell Recruitment

Brucella abortus is a zoonotic pathogen that causes brucellosis. Because of Brucella’s unique LPS layer and intracellular localization predominately within macrophages, it can often evade immune detection. However, pattern recognition receptors are capable of sensing Brucella pathogen-associated molecular patterns (PAMPS). For example, NOD-like receptors (NLRs) can form a multi-protein inflammasome complex to attenuate Brucella pathogenesis. The inflammasome activates IL-1β and IL-18 to drive immune cell recruitment. Alternatively, inflammasome activation also initiates inflammatory cell death, termed pyroptosis, which augments bacteria clearance. In this report, we assess canonical and non-canonical inflammasome activation following B. abortus infection. We conducted in vivo studies using Asc−/− mice and observed decreased mouse survival, immune cell recruitment, and increased bacteria load. We also conducted studies with Caspase-11−/− mice and did not observe any significant impact on B. abortus pathogenesis. Through mechanistic studies using Asc−/− macrophages, our data suggests that the protective role of ASC may result from the induction of pyroptosis through a gasdermin D-dependent mechanism in macrophages. Additionally, we show that the recognition of Brucella is facilitated by sensing the PAMP gDNA rather than the less immunogenic LPS. Together, these results refine our understanding of the role that inflammasome activation and pyroptosis plays during brucellosis.

scholarly journals Plasminogen Receptors and Fibrinolysis

2021 ◽  
Vol 22 (4) ◽  
pp. 1712
Author(s):  
Lindsey A. Miles ◽  
Lina Ny ◽  
Malgorzata Wilczynska ◽  
Yue Shen ◽  
Tor Ny ◽  
...  
Keyword(s):  
Immune Cell ◽  
Surface Proteins ◽  
Eukaryotic Cells ◽  
Plasminogen Activation ◽  
Murine Models ◽  
Cell Surface Proteins ◽  
Cell Recruitment ◽  
Distinct Cell ◽  
Immune Cell Recruitment

The ability of cells to promote plasminogen activation on their surfaces is now well recognized, and several distinct cell surface proteins have been demonstrated to function as plasminogen receptors. Here, we review studies demonstrating that plasminogen bound to cells, in addition to plasminogen directly bound to fibrin, plays a major role in regulating fibrin surveillance. We focus on the ability of specific plasminogen receptors on eukaryotic cells to promote fibrinolysis in the in vivo setting by reviewing data obtained predominantly in murine models. Roles for distinct plasminogen receptors in fibrin surveillance in intravascular fibrinolysis, immune cell recruitment in the inflammatory response, wound healing, and lactational development are discussed.

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