Chondrocytes from Osteoarthritis Patients Adopt Distinct Phenotypes in Response to Central TH1/TH2/TH17 Cytokines

Chronic low-grade inflammation plays a central role in the pathogenesis of osteoarthritis (OA), and several pro- and anti-inflammatory cytokines have been implicated to mediate and regulate this process. Out of these cytokines, particularly IFNγ, IL-1β, IL-4 and IL-17 are associated with different phenotypes of T helper (TH) cells and macrophages, both examples of cells known for great phenotypic and functional heterogeneity. Chondrocytes also display various phenotypic changes during the course of arthritis. We set out to study the hypothesis of whether chondrocytes might adopt polarized phenotypes analogous to TH cells and macrophages. We studied the effects of IFNγ, IL-1β, IL-4 and IL-17 on gene expression in OA chondrocytes with RNA-Seq. Chondrocytes were harvested from the cartilage of OA patients undergoing knee replacement surgery and then cultured with or without the cytokines for 24 h. Total RNA was isolated and sequenced, and GO (Gene Ontology) functional analysis was performed. We also separately investigated genes linked to OA in recent genome wide expression analysis (GWEA) studies. The expression of more than 2800 genes was significantly altered in chondrocytes treated with IL-1β [in the C(IL-1β) phenotype] with a fold change (FC) > 2.5 in either direction. These included a large number of genes associated with inflammation, cartilage degradation and attenuation of metabolic signaling. The profile of genes differentially affected by IFNγ (the C(IFNγ) phenotype) was relatively distinct from that of the C(IL-1β) phenotype and included several genes associated with antigen processing and presentation. The IL-17-induced C(IL-17) phenotype was characterized by the induction of a more limited set of proinflammatory factors compared to C(IL-1β) cells. The C(IL-4) phenotype induced by IL-4 displayed a differential expression of a rather small set of genes compared with control, primarily those associated with TGFβ signaling and the regulation of inflammation. In conclusion, our results show that OA chondrocytes can adopt diverse phenotypes partly analogously to TH cells and macrophages. This phenotypic plasticity may play a role in the pathogenesis of arthritis and open new therapeutic avenues for the development of disease-modifying treatments for (osteo)arthritis.

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Widespread regulation of gene expression by glucocorticoids in chondrocytes from patients with osteoarthritis as determined by RNA-Seq

Arthritis Research & Therapy ◽

10.1186/s13075-020-02289-7 ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Antti Pemmari ◽

Tiina Leppänen ◽

Mari Hämäläinen ◽

Teemu Moilanen ◽

Katriina Vuolteenaho ◽

...

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression ◽

Symptomatic Treatment ◽

Metabolic Phenotype ◽

Rna Seq ◽

Chondrocyte Phenotype ◽

Replacement Surgery ◽

Genome Wide ◽

Matrix Organization ◽

Oa Chondrocytes

Abstract Background Intra-articular glucocorticoid (GC) injections are widely used as a symptomatic treatment for osteoarthritis (OA). However, there are also concerns about their potentially harmful effects, and their detailed effects on chondrocyte phenotype remain poorly understood. Methods We studied the effects of dexamethasone on gene expression in OA chondrocytes with RNA-Seq. Chondrocytes were isolated from the cartilage from OA patients undergoing knee replacement surgery and cultured with or without dexamethasone for 24 h. Total RNA was isolated and sequenced, and functional analysis was performed against the Gene Ontology (GO) database. Results for selected genes were confirmed with RT-PCR. We also investigated genes linked to OA in recent genome-wide expression analysis (GWEA) studies. Results Dexamethasone increased the expression of 480 and reduced that of 755 genes with a fold change (FC) 2.0 or greater. Several genes associated with inflammation and cartilage anabolism/catabolism as well as lipid and carbohydrate metabolism were among the most strongly affected genes. In the GO analysis, genes involved in the extracellular matrix organization, cell proliferation and adhesion, inflammation, and collagen synthesis were enriched among the significantly affected genes. In network analysis, NGF, PI3KR1, and VCAM1 were identified as central genes among those most strongly affected by dexamethasone. Conclusions This is the first study investigating the genome-wide effects of GCs on the gene expression in OA chondrocytes. In addition to clear anti-inflammatory and anticatabolic effects, GCs affect lipid and glucose metabolism in chondrocytes, an observation that might be particularly important in the metabolic phenotype of OA.

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CD8+ T cell escape of HCV by selection of a polymorphism in the epitope flanking region that impairs antigen processing and presentation

Zeitschrift für Gastroenterologie ◽

10.1055/s-0032-1332185 ◽

2013 ◽

Vol 51 (01) ◽

Author(s):

A Walker ◽

K Skibbe ◽

S Groten ◽

V Lüger ◽

M Ruhl ◽

...

Keyword(s):

T Cell ◽

Antigen Processing ◽

Cd8 T Cell ◽

Flanking Region ◽

Antigen Processing And Presentation ◽

Selection Of

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Faculty Opinions recommendation of Mechanisms of HLA-DP Antigen Processing and Presentation Revisited.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734424585.793554889 ◽

2019 ◽

Author(s):

Jacques Thibodeau

Keyword(s):

Antigen Processing ◽

Antigen Processing And Presentation

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Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs

Cancers ◽

10.3390/cancers13071674 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1674

Author(s):

Sara Tomei ◽

Ola Ibnaof ◽

Shilpa Ravindran ◽

Soldano Ferrone ◽

Cristina Maccalli

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Immune Responses ◽

Antigen Processing ◽

Aberrant Expression ◽

Immunological Profile ◽

Malignant Lesions ◽

Novel Therapeutic Strategies ◽

Antigen Processing And Presentation

Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.

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The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes

Scientific Reports ◽

10.1038/s41598-021-95009-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ilona E. Grabowicz ◽

Bartek Wilczyński ◽

Bożena Kamińska ◽

Adria-Jaume Roura ◽

Bartosz Wojtaś ◽

...

Keyword(s):

Gene Expression ◽

Long Range ◽

Genetic Alterations ◽

Chromatin Organization ◽

Open Chromatin ◽

Low Grade ◽

Strong Impact ◽

Cell Matrix ◽

Topologically Associating Domains ◽

Genome Wide

AbstractGenome-wide studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different glioma types. We have recently created a unique atlas encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we intersected genome-wide atlas data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in WHO low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found the set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing specific glioma-related genes. Moreover, many genes associated with the cell–matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by long-range contacts with enhancers. Presented results demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy.

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Cysteine Cathepsins and Their Prognostic and Therapeutic Relevance in Leukemia

Annals of the National Academy of Medical Sciences (India) ◽

10.1055/s-0041-1726151 ◽

2021 ◽

Author(s):

Mohit Arora ◽

Garima Pandey ◽

Shyam S. Chauhan

Keyword(s):

Antigen Processing ◽

Hematological Malignancies ◽

Expression Patterns ◽

Aberrant Expression ◽

Hematopoietic Stem ◽

Cysteine Cathepsins ◽

Expression Activity ◽

Available Information ◽

Antigen Processing And Presentation ◽

Selection Of

AbstractCysteine cathepsins are lysosomal proteases that require Cys-His ion pair in their catalytic site for enzymatic activity. While their aberrant expression and oncogenic functions have been widely reported in solid tumors, recent findings suggest that these proteases also play an important role in the pathogenesis of hematological malignancies. In this review, we summarize the potential clinical implications of cysteine cathepsins as diagnostic and prognostic markers in leukemia, and present evidences which supports the utility of these proteases as potential therapeutic targets in hematological malignancies. We also highlight the available information on the expression patterns, regulation, and potential functions of cysteine cathepsins in normal hematopoiesis and hematological malignancies. In hematopoiesis, cysteine cathepsins play a variety of physiological roles including regulation of hematopoietic stem cell adhesion in the bone marrow, trafficking, and maturation. They are also involved in several functions of immune cells which include the selection of lymphocytes in the thymus, antigen processing, and presentation. However, the expression of cysteine cathepsins is dysregulated in hematological malignancies where they have been shown to play diverse functions. Interestingly, several pieces of evidence over the past few years have demonstrated overexpression of cathepsins in leukemia and their association with worst survival outcomes in patients. Strategies aimed at altering the expression, activity, and subcellular localization of these cathepsins are emerging as potential therapeutic modalaties in the management of hematological malignancies. Recent findings also suggest the involvement of these proteases in modulating the immune response in leukemia and lymphomas.

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Regulation of protein synthesis and autophagy in activated dendritic cells: implications for antigen processing and presentation

Immunological Reviews ◽

10.1111/imr.12427 ◽

2016 ◽

Vol 272 (1) ◽

pp. 28-38 ◽

Cited By ~ 12

Author(s):

Rafael J. Argüello ◽

Marisa Reverendo ◽

Evelina Gatti ◽

Philippe Pierre

Keyword(s):

Dendritic Cells ◽

Protein Synthesis ◽

Antigen Processing ◽

Antigen Processing And Presentation

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Antigen processing and presentation

Tissue Antigens ◽

10.1111/j.1399-0039.1996.tb02587.x ◽

1996 ◽

Vol 47 (6) ◽

pp. 464-471 ◽

Cited By ~ 28

Author(s):

F. M. Brodsky ◽

L. Lem ◽

P. A. Bresnahan

Keyword(s):

Antigen Processing ◽

Antigen Processing And Presentation

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Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells

Journal of Innate Immunity ◽

10.1159/000450681 ◽

2016 ◽

Vol 9 (2) ◽

pp. 126-144 ◽

Cited By ~ 6

Author(s):

Yaping Sun ◽

Matthew Iyer ◽

Richard McEachin ◽

Meng Zhao ◽

Yi-Mi Wu ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Histone Deacetylase ◽

Antigen Processing ◽

Target Genes ◽

Hdac Inhibition ◽

Histone Deacetylase Inhibition ◽

Immune Effector ◽

Chip Sequencing ◽

Genome Wide

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.

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