Publications by authors named "George Kollias"

180 Publications

Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis.

J Clin Invest 2021 Mar;131(6)

Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

In rheumatoid arthritis (RA), osteoclastic bone resorption causes structural joint damage as well as periarticular and systemic bone loss. Periarticular bone loss is one of the earliest indices of RA, often preceding the onset of clinical symptoms via largely unknown mechanisms. Excessive osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) expressed by synovial fibroblasts causes joint erosion, whereas the role of RANKL expressed by lymphocytes in various types of bone damage has yet to be elucidated. In the bone marrow of arthritic mice, we found an increase in the number of RANKL-expressing plasma cells, which displayed an ability to induce osteoclastogenesis in vitro. Genetic ablation of RANKL in B-lineage cells resulted in amelioration of periarticular bone loss, but not of articular erosion or systemic bone loss, in autoimmune arthritis. We also show conclusive evidence for the critical contribution of synovial fibroblast RANKL to joint erosion in collagen-induced arthritis on the arthritogenic DBA/1J background. This study highlights the importance of plasma-cell RANKL in periarticular bone loss in arthritis and provides mechanistic insight into the early manifestation of bone lesion induced by autoimmunity.
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http://dx.doi.org/10.1172/JCI143060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954598PMC
March 2021

Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity.

Nat Immunol 2021 Apr 11;22(4):510-519. Epub 2021 Mar 11.

Institute for Bioinnovation, BSRC "Alexander Fleming", Vari, Greece.

Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.
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http://dx.doi.org/10.1038/s41590-021-00894-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610542PMC
April 2021

'SMASH' recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal models.

Ann Rheum Dis 2021 Feb 18. Epub 2021 Feb 18.

Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Animal models for inflammatory arthritides such as rheumatoid arthritis (RA) and psoriatic arthritis are widely accepted and frequently used to identify pathological mechanisms and validate novel therapeutic strategies. Unfortunately, many publications reporting on these animal studies lack detailed description and appropriate assessment of the distinct histopathological features of arthritis: joint inflammation, cartilage damage and bone erosion. Therefore, the European consortium BeTheCure, consisting of 38 academic and industrial partners from 15 countries, set as goal to standardise the histological evaluation of joint sections from animal models of inflammatory arthritis. The consensual approach of a task force including 16 academic and industrial scientists as well as laboratory technicians has resulted in the development of the Standardised Microscopic Arthritis Scoring of Histological sections ('SMASH') recommendations for a standardised processing and microscopic scoring of the characteristic histopathological features of arthritis, exemplified by four different rodent models for arthritis: murine collagen-induced arthritis, collagen-antibody-induced arthritis, human tumour necrosis factor transgenic Tg197 mice and rat pristane-induced arthritis, applicable to any other inflammatory arthritis model. Through standardisation, the SMASH recommendations are designed to improve and maximise the information derived from in vivo arthritis experiments and to promote reproducibility and transparent reporting on such studies. In this manuscript, we will discuss and provide recommendations for analysis of histological joint sections: identification of the regions of interest, sample preparation, staining procedures and quantitative scoring methods. In conclusion, awareness of the different features of the arthritis pathology in animal models of inflammatory arthritis is of utmost importance for reliable research outcome, and the standardised histological processing and scoring methods in these SMASH recommendations will help increase uniformity and reproducibility in preclinical research on inflammatory arthritis.
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http://dx.doi.org/10.1136/annrheumdis-2020-219247DOI Listing
February 2021

Distinct transcriptional profile of blood mononuclear cells in Behcet's disease: insights into the central role of neutrophil chemotaxis.

Rheumatology (Oxford) 2021 Jan 25. Epub 2021 Jan 25.

Center of New Biotechnologies & Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.

Objectives: Both innate and adaptive immune responses are reportedly increased in Behcet's disease (BD), a chronic-relapsing systemic vasculitis lying at the intersection between autoinflammation and autoimmunity. To further study pathophysiologic molecular mechanisms operating in BD we searched for transcriptome-wide changes in blood mononuclear cells from these patients.

Methods: We performed 3' mRNA next generation sequencing-based genome-wide transcriptional profiling followed by analysis of differential expression signatures, KEGG pathways, GO biological processes and transcription factor signatures.

Results: Differential expression analysis clustered the transcriptomes of 13 patients and one healthy subject apart from those of 10 healthy age/gender-matched controls and one patient. Among the total of 17,591 expressed protein coding genes, 209 and 31 genes were significantly up- and down-regulated, respectively, in BD versus controls by at least 2-fold. The most up-regulated genes comprised an abundance of CC- and CXC-chemokines. Remarkably, the 5 out of top 10 up-regulated biological processes involved leukocyte recruitment to peripheral tissues, especially for neutrophils. Moreover, NF-kB, TNF and IL-1 signaling pathways were prominently enhanced in BD, while transcription factor activity analysis suggested that the NF-kB p65/RELA subunit action underlies the observed differences in the BD transcriptome.

Conclusion: This RNA-sequencing analysis in PBMCs derived from patients with BD does not support a major pathogenetic role of adaptive immunity-driven mechanisms, but clearly points to the action of aberrant innate immune responses with a central role of up-regulated neutrophil chemotaxis.
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http://dx.doi.org/10.1093/rheumatology/keab052DOI Listing
January 2021

TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFα antibodies.

Cardiovasc Res 2021 Jan 23. Epub 2021 Jan 23.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Switzerland.

Aims: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and blood vessels. Despite low levels of low-density lipoprotein cholesterol (LDL-C), RA patients exhibit endothelial dysfunction and are at increased risk of death from cardiovascular (CV) complications, but the molecular mechanism of action is unknown.We aimed in the present study to identify the molecular mechanism of endothelial dysfunction in a mouse model of RA and in patients with RA.

Methods And Results: Endothelium-dependent relaxations to acetylcholine were reduced in aortae of two TNFα transgenic mouse lines with either mild (Tg3647) or severe (Tg197) forms of RA in a time- and severity-dependent fashion as assessed by organ chamber myograph. In Tg197, TNFα plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly upregulated leading to increased vascular oxLDL uptake and NFκB-mediated enhanced Arg2 expression via direct binding to its promoter resulting in reduced NO bioavailability and vascular cGMP levels as shown by ELISA and chromatin immunoprecipitation. Anti-TNFα treatment with infliximab normalized endothelial function together with LOX-1 and Arg2 serum levels in mice. In RA patients, soluble LOX-1 serum levels were also markedly increased and closely related to serum levels of C-reactive protein. Similarly, ARG2 serum levels were increased. Similarly, anti-TNFα treatment restored LOX-1 and ARG2 serum levels in RA patients.

Conclusions: Increased TNFα levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NFκB/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNFα treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL and Arg2 levels.
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http://dx.doi.org/10.1093/cvr/cvab005DOI Listing
January 2021

DENTAL DISEASES AND OTHER ORAL PATHOLOGIES OF CAPTIVE JAGUARS () FROM BELIZE, CENTRAL AMERICA.

J Zoo Wildl Med 2021 Jan;51(4):856-867

Department of Clinical Sciences, Cornell University, NY 14853, USA,

Dental and oral diseases are prevalent in many mammalian species including wild felids. Determining the dental and oral health status of captive animal populations can help establish preventive and therapeutic strategies, leading to improved welfare and conservation efforts. The aim of this study was to assess the prevalence of periodontal disease, endodontic disease, tooth resorption, and other clinically relevant dental and maxillofacial abnormalities in a population of captive jaguars () using clinical, radiographic, and histopathological findings. Fifteen jaguars, ranging from young adult to geriatric, kept at a private zoo in Belize, Central America, had a detailed oral examination under general anesthesia between January 2015 and March 2019. Periodontitis was present in 3.8% (16/423) of examined teeth and 53.8% (7/13) of jaguars that underwent periodontal probing. Endodontic disease secondary to dentoalveolar trauma was found in 21.0% (89/423) of teeth in 73.3% (11/15) of animals. Tooth resorption, which has not been previously documented in jaguars, affected 1.4% (6/423) of teeth in 13.3% (2/15) of jaguars. Other abnormalities included metallic foreign material (gunshot) identified radiographically in 33.3% (5/15) of jaguars and nontraumatizing malocclusion in 9.1% (1/11) of jaguars that had occlusion evaluated. Much of the oral pathology identified in captive jaguars is suspected to arise from capture and/or captivity-associated behaviors, as suggested by gunshot around the oral cavity, fractures of rostral teeth (canine and incisor teeth), and abrasions consistent with cage-biting on canine teeth. Anesthetized oral examination-including full-mouth intraoral radiographs, periodontal probing, and charting-is recommended for jaguars with clinical signs of oral pain, as well as for routine systemic evaluation.
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http://dx.doi.org/10.1638/2019-0222DOI Listing
January 2021

Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis.

Arthritis Res Ther 2020 10 6;22(1):232. Epub 2020 Oct 6.

Institute of Immunology, Biomedical Sciences Research Center (BSRC), 'Alexander Fleming', 34 Alexander Fleming Street, 16672, Vari, Greece.

Background: The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model.

Methods: TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis.

Results: TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice.

Conclusions: The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.
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http://dx.doi.org/10.1186/s13075-020-02327-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542121PMC
October 2020

The mesenchymal context in inflammation, immunity and cancer.

Nat Immunol 2020 09 3;21(9):974-982. Epub 2020 Aug 3.

Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.

Mesenchymal cells are mesoderm-derived stromal cells that are best known for providing structural support to organs, synthesizing and remodeling the extracellular matrix (ECM) and regulating development, homeostasis and repair of tissues. Recent detailed mechanistic insights into the biology of fibroblastic mesenchymal cells have revealed they are also significantly involved in immune regulation, stem cell maintenance and blood vessel function. It is now becoming evident that these functions, when defective, drive the development of complex diseases, such as various immunopathologies, chronic inflammatory disease, tissue fibrosis and cancer. Here, we provide a concise overview of the contextual contribution of fibroblastic mesenchymal cells in physiology and disease and bring into focus emerging evidence for both their heterogeneity at the single-cell level and their tissue-specific, spatiotemporal functional diversity.
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http://dx.doi.org/10.1038/s41590-020-0741-2DOI Listing
September 2020

Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis.

J Exp Med 2020 10;217(10)

Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.

TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproliferative inflammation in SpA. We observed a marked increase of transmembrane (tm) versus soluble (s) TNF in SpA versus RA together with a decrease in the enzymatic activity of ADAM17. In contrast with the destructive polysynovitis observed in classical TNF overexpression models, mice overexpressing tmTNF developed axial and peripheral joint disease with synovitis, enthesitis, and osteitis. Histological and radiological assessment evidenced marked endochondral new bone formation leading to joint ankylosis over time. SpA-like inflammation, but not osteoproliferation, was dependent on TNF-receptor I and mediated by stromal tmTNF overexpression. Collectively, these data indicate that TNF can drive distinct inflammatory pathologies. We propose that tmTNF is responsible for the key pathological features of SpA.
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http://dx.doi.org/10.1084/jem.20200288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537402PMC
October 2020

Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche.

Nature 2020 04 1;580(7804):524-529. Epub 2020 Apr 1.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E (PGE). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE drives the expansion οf a population of Sca-1 reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1 cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1 cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE-Ptger4. Analyses of patient-derived organoids established that PGE-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE-Ptger4-Yap signalling axis.
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http://dx.doi.org/10.1038/s41586-020-2166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490650PMC
April 2020

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis.

PLoS One 2020 2;15(4):e0226050. Epub 2020 Apr 2.

Biomedical Sciences Research Center Alexander Fleming, Athens, Greece.

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117669PMC
July 2020

Reel syndrome-An uncommon etiology of ICD dysfunction.

Clin Case Rep 2020 Mar 30;8(3):582-583. Epub 2020 Jan 30.

Department of Cardiology, Electrophysiology Laboratory Evangelismos General Hospital of Athens Athens Greece.

Reel syndrome occurs due to the rotation of the implantable device on its transverse axis with subsequent coiling of the leads around the pulse generator. Device interrogation and chest X-ray should be performed in any case of device malfunction.
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http://dx.doi.org/10.1002/ccr3.2682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069861PMC
March 2020

Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme.

J Exp Med 2020 04;217(4)

Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.

Innate mechanisms in the tumor stroma play a crucial role both in the initial rejection of tumors and in cancer promotion. Here, we provide a concise overview of the innate system in cancer and recent advances in the field, including the activation and functions of innate immune cells and the emerging innate properties and modulatory roles of the fibroblastic mesenchyme. Novel insights into the diverse identities and functions of the innate immune and mesenchymal cells in the microenvironment of tumors should lead to improved anticancer therapies.
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http://dx.doi.org/10.1084/jem.20190457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144533PMC
April 2020

STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis.

Gut 2020 07 4;69(7):1269-1282. Epub 2019 Nov 4.

First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany

Objective: Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood.

Design: We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI-) on STAT3 activation (IL-6 vs IL-11).

Results: The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts.

Conclusion: Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.
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http://dx.doi.org/10.1136/gutjnl-2019-319200DOI Listing
July 2020

The BACH1-HMOX1 Regulatory Axis Is Indispensable for Proper Macrophage Subtype Specification and Skeletal Muscle Regeneration.

J Immunol 2019 09 12;203(6):1532-1547. Epub 2019 Aug 12.

Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL 33701;

The infiltration and subsequent in situ subtype specification of monocytes to effector/inflammatory and repair macrophages is indispensable for tissue repair upon acute sterile injury. However, the chromatin-level mediators and regulatory events controlling this highly dynamic macrophage phenotype switch are not known. In this study, we used a murine acute muscle injury model to assess global chromatin accessibility and gene expression dynamics in infiltrating macrophages during sterile physiological inflammation and tissue regeneration. We identified a heme-binding transcriptional repressor, BACH1, as a novel regulator of this process. knockout mice displayed impaired muscle regeneration, altered dynamics of the macrophage phenotype transition, and transcriptional deregulation of key inflammatory and repair-related genes. We also found that BACH1 directly binds to and regulates distal regulatory elements of these genes, suggesting a novel role for BACH1 in controlling a broad spectrum of the repair response genes in macrophages upon injury. Inactivation of heme oxygenase-1 (), one of the most stringently deregulated genes in the knockout in macrophages, impairs muscle regeneration by changing the dynamics of the macrophage phenotype switch. Collectively, our data suggest the existence of a heme-BACH1--HMOX1 regulatory axis, that controls the phenotype and function of the infiltrating myeloid cells upon tissue damage, shaping the overall tissue repair kinetics.
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http://dx.doi.org/10.4049/jimmunol.1900553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736746PMC
September 2019

A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain.

Nat Cell Biol 2019 06 13;21(6):731-742. Epub 2019 May 13.

Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine, University of Cologne, Cologne, Germany.

Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signalling, cell death and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function. Here we show that A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7). We provide genetic evidence that RIPK1 kinase-dependent, RIPK3-MLKL-mediated necroptosis drives inflammasome activation in A20-deficient macrophages and causes inflammatory arthritis in mice. Single-cell imaging revealed that RIPK3-dependent death caused inflammasome-dependent IL-1β release from lipopolysaccharide-stimulated A20-deficient macrophages. Importantly, mutation of the A20 ZnF7 ubiquitin binding domain caused arthritis in mice, arguing that ZnF7-dependent inhibition of necroptosis is critical for A20 anti-inflammatory function in vivo.
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http://dx.doi.org/10.1038/s41556-019-0324-3DOI Listing
June 2019

An integrative transcriptome analysis framework for drug efficacy and similarity reveals drug-specific signatures of anti-TNF treatment in a mouse model of inflammatory polyarthritis.

PLoS Comput Biol 2019 05 9;15(5):e1006933. Epub 2019 May 9.

Department of Biology, University of Crete, Heraklion, Greece.

Anti-TNF agents have been in the first line of treatment of various inflammatory diseases such as Rheumatoid Arthritis and Crohn's Disease, with a number of different biologics being currently in use. A detailed analysis of their effect at transcriptome level has nevertheless been lacking. We herein present a concise analysis of an extended transcriptomics profiling of four different anti-TNF biologics upon treatment of the established hTNFTg (Tg197) mouse model of spontaneous inflammatory polyarthritis. We implement a series of computational analyses that include clustering of differentially expressed genes, functional analysis and random forest classification. Taking advantage of our detailed sample structure, we devise metrics of treatment efficiency that take into account changes in gene expression compared to both the healthy and the diseased state. Our results suggest considerable variability in the capacity of different biologics to modulate gene expression that can be attributed to treatment-specific functional pathways and differential preferences to restore over- or under-expressed genes. Early intervention appears to manage inflammation in a more efficient way but is accompanied by increased effects on a number of genes that are seemingly unrelated to the disease. Administration at an early stage is also lacking in capacity to restore healthy expression levels of under-expressed genes. We record quantifiable differences among anti-TNF biologics in their efficiency to modulate over-expressed genes related to immune and inflammatory pathways. More importantly, we find a subset of the tested substances to have quantitative advantages in addressing deregulation of under-expressed genes involved in pathways related to known RA comorbidities. Our study shows the potential of transcriptomic analyses to identify comprehensive and distinct treatment-specific gene signatures combining disease-related and unrelated genes and proposes a generalized framework for the assessment of drug efficacy, the search of biosimilars and the evaluation of the efficacy of TNF small molecule inhibitors.
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http://dx.doi.org/10.1371/journal.pcbi.1006933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508611PMC
May 2019

RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury.

Cell Death Differ 2019 Dec 15;26(12):2710-2726. Epub 2019 Apr 15.

Institute for Genetics, University of Cologne, D-50674, Cologne, Germany.

Hepatocyte apoptosis is intrinsically linked to chronic liver disease and hepatocarcinogenesis. Conversely, necroptosis of hepatocytes and other liver cell types and its relevance for liver disease is debated. Using liver parenchymal cell (LPC)-specific TGF-beta-activated kinase 1 (TAK1)-deficient (TAK1) mice, which exhibit spontaneous hepatocellular and biliary damage, hepatitis, and early hepatocarcinogenesis, we have investigated the contribution of apoptosis and necroptosis in hepatocyte and cholangiocyte death and their impact on liver disease progression. Here, we provide in vivo evidence showing that TAK1-deficient cholangiocytes undergo spontaneous necroptosis induced primarily by TNFR1 and dependent on RIPK1 kinase activity, RIPK3, and NEMO. In contrast, TAK1-deficient hepatocytes die by FADD-dependent apoptosis, which is not significantly inhibited by LPC-specific RIPK1 deficiency, inhibition of RIPK1 kinase activity, RIPK3 deficiency or combined LPC-specific deletion of TNFR1, TRAILR, and Fas. Accordingly, normal mouse cholangiocytes can undergo necroptosis, while primary hepatocytes are resistant to it and die exclusively by apoptosis upon treatment with cell death-inducing stimuli in vitro, likely due to the differential expression of RIPK3. Interestingly, the genetic modifications that conferred protection from biliary damage also prevented the spontaneous lethality that was often observed in TAK1 mice. In the presence of chronic hepatocyte apoptosis, preventing biliary damage delayed but did not avert hepatocarcinogenesis. On the contrary, inhibition of hepatocyte apoptosis fully prevented liver tumorigenesis even in mice with extensive biliary damage. Altogether, our results suggest that using RIPK1 kinase activity inhibitors could be therapeutically useful for cholestatic liver disease patients.
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http://dx.doi.org/10.1038/s41418-019-0330-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861136PMC
December 2019

Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma.

Nat Commun 2019 03 29;10(1):1405. Epub 2019 Mar 29.

Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece.

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.
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http://dx.doi.org/10.1038/s41467-019-09370-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441097PMC
March 2019

Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis.

Cell Rep 2019 01;26(3):536-545.e4

Biomedical Sciences Research Centre (BSRC) "Alexander Fleming," Vari 16672, Greece; Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece. Electronic address:

MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apc model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not interleukin-1 receptor (IL-1R), in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis in IMCs indicated that these effects could be mediated through downstream signals involving growth factors and inflammatory and extracellular matrix (ECM)-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and promote carcinogenesis in the intestine.
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http://dx.doi.org/10.1016/j.celrep.2018.12.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334226PMC
January 2019

Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation.

Gastroenterology 2019 03 16;156(4):1082-1097.e11. Epub 2018 Nov 16.

First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

Background & Aims: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice.

Methods: We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control individuals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2 mice; colitis and fibrosis were induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2 to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied.

Results: Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control individuals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2 mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis after administration of DSS or TNBS, but bone marrow cells from Il1rl2 mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation.

Conclusion: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control individuals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.
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http://dx.doi.org/10.1053/j.gastro.2018.11.029DOI Listing
March 2019

Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis.

Nat Commun 2018 11 5;9(1):4613. Epub 2018 Nov 5.

Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Technologiepark 927, 9052, Ghent, Belgium.

Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. The reason behind the regional and patchy distribution of arthritis represents a longstanding paradox. Here we show that biomechanical loading acts as a decisive factor in the transition from systemic autoimmunity to joint inflammation. Distribution of inflammation and erosive disease is confined to mechano-sensitive regions with a unique microanatomy. Curiously, this pathway relies on stromal cells but not adaptive immunity. Mechano-stimulation of mesenchymal cells induces CXCL1 and CCL2 for the recruitment of classical monocytes, which can differentiate into bone-resorbing osteoclasts. Genetic ablation of CCL2 or pharmacologic targeting of its receptor CCR2 abates mechanically-induced exacerbation of arthritis, indicating that stress-induced chemokine release by mesenchymal cells and chemo-attraction of monocytes determines preferential homing of arthritis to certain hot spots. Thus, mechanical strain controls the site-specific localisation of inflammation and tissue damage in arthritis.
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http://dx.doi.org/10.1038/s41467-018-06933-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218475PMC
November 2018

Introduction to Mammalian Genome special issue: inflammation and immunity in cancer.

Mamm Genome 2018 12;29(11-12):691-693

Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.

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http://dx.doi.org/10.1007/s00335-018-9787-yDOI Listing
December 2018

Discovery of Plant-Origin Natural Product Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).

Front Pharmacol 2018 25;9:800. Epub 2018 Jul 25.

Division of Immunology Biomedical Sciences Research Center "Alexander Fleming,", Vari, Greece.

An drug discovery pipeline for the virtual screening of plant-origin natural products (NPs) was developed to explore new direct inhibitors of TNF and its close relative receptor activator of nuclear factor kappa-B ligand (RANKL), both representing attractive therapeutic targets for many chronic inflammatory conditions. Direct TNF inhibition through identification of potent small molecules is a highly desired goal; however, it is often hampered by severe limitations. Our approach yielded a priority list of 15 NPs as potential direct TNF inhibitors that were subsequently tested against TNF and RANKL. We thus identified two potent direct inhibitors of TNF function with low micromolar IC values and minimal toxicity even at high concentrations. Most importantly, one of them (A11) was proved to be a dual inhibitor of both TNF and RANKL. Extended molecular dynamics simulations with the fully automated EnalosMD suite rationalized the mode of action of the compounds at the molecular level. To our knowledge, these compounds constitute the first NP TNF inhibitors, one of which being the first NP small-molecule dual inhibitor of TNF and RANKL, and could serve as lead compounds for the development of novel treatments for inflammatory and autoimmune diseases.
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http://dx.doi.org/10.3389/fphar.2018.00800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068282PMC
July 2018

Cigarette Smoke-Induced Emphysema Exhausts Early Cytotoxic CD8 T Cell Responses against Nascent Lung Cancer Cells.

J Immunol 2018 09 23;201(5):1558-1569. Epub 2018 Jul 23.

Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming,' 16672 Vari, Athens, Greece;

Chronic obstructive pulmonary disease is a chronic inflammatory disorder with an increased incidence of lung cancer. The emphysema component of chronic obstructive pulmonary disease confers the greatest proportion to lung cancer risk. Although tumors create inflammatory conditions to escape immunity, the immunological responses that control growth of nascent cancer cells in pre-established inflammatory microenvironments are unknown. In this study, we addressed this issue by implanting OVA-expressing cancer cells in the lungs of mice with cigarette smoke-induced emphysema. Emphysema augmented the growth of cancer cells, an effect that was dependent on T cytotoxic cells. OVA-specific OTI T cells showed early signs of exhaustion upon transfer in emphysema tumor hosts that was largely irreversible because sorting, expansion, and adoptive transfer failed to restore their antitumor activity. Increased numbers of PD-L1- and IDO-positive CD11c myeloid dendritic cells (DCs) infiltrated emphysema tumors, whereas sorted emphysema tumor DCs poorly stimulated OTI T cells. Upon adoptive transfer in immunocompetent hosts, T cells primed by emphysema tumor DCs were unable to halt tumor growth. DCs exposed to the emphysema tumor microenvironment downregulated MHC class II and costimulatory molecules, whereas they upregulated PD-L1/IDO via oxidative stress-dependent mechanisms. T cell activation increased upon PD-L1 blockade in emphysema DC-T cell cocultures and in emphysema tumor hosts in vivo. Analysis of the transcriptome of primary human lung tumors showed a strong association between computed tomography-based emphysema scoring and downregulation of immunogenic processes. Thus, suppression of adaptive immunity against lung cancer cells links a chronic inflammatory disorder, emphysema, to cancer, with clinical implications for emphysema patients to be considered optimal candidates for cancer immunotherapies.
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http://dx.doi.org/10.4049/jimmunol.1700700DOI Listing
September 2018

HYPERKALEMIA IN TWO JAGUARS ( PANTHERA ONCA) ANESTHETIZED WITH DEXMEDETOMIDINE, KETAMINE, AND ISOFLURANE.

J Zoo Wildl Med 2018 Jun;49(2):505-507

  Two jaguars were anesthetized with dexmedetomidine, ketamine, and isoflurane. Arterial blood samples analyzed shortly after darting revealed no abnormalities. Samples analyzed 2 and 1.5 hr after darting revealed moderate hyperkalemia in both animals (6.8 and 6.2 mEq/L, respectively). Shortly after hyperkalemia was recognized, one jaguar developed electrocardiographic abnormalities (sinoventricular rhythm and widened QRS complexes), and a few minutes later, suffered cardiopulmonary arrest. Resuscitation with chest compressions, intermittent positive-pressure ventilation, and epinephrine was successful, and autonomous breathing and circulation resumed within a few minutes. Anesthesia-related hyperkalemia has been reported in a variety of large felids but has not been reported previously in jaguars. In all reports, α-2 adrenergic agonists were used as part of the immobilization protocol. Due to the presumptively high incidence and mortality caused by this complication, frequent monitoring of electrolyte concentrations and prompt treatment of hyperkalemia is recommended when anesthetizing large felids, including jaguars.
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http://dx.doi.org/10.1638/2017-0147.1DOI Listing
June 2018

Current Status and Future Prospects of Small-molecule Protein-protein Interaction (PPI) Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).

Curr Top Med Chem 2018 ;18(8):661-673

NovaMechanics Ltd, Nicosia, Cyprus.

The overexpression of Tumor Necrosis Factor (TNF) is directly related to the development of several autoimmune diseases, such as rheumatoid and psoriatic arthritis, inflammatory bowel disease, Crohn's disease, refractory asthma, and multiple sclerosis. Receptor Activator of Nuclear Factor Kappa- B Ligand (RANKL) belongs to the TNF family and is the primary mediator of osteoclast-induced bone resorption through interaction with its receptor RANK. The function of RANKL is physiologically inhibited by the action of osteoprotegerin (OPG), which is a decoy receptor that binds to RANKL and prevents the process of osteoclastogenesis. Malfunction among RANK/RANKL/OPG can also result in bone loss diseases, including postmenopausal osteoporosis, rheumatoid arthritis, bone metastasis and multiple myeloma. To disrupt the unwanted functions of TNF and RANKL, current attempts focus on blocking TNF and RANKL binding to their receptors. In this review, we present the research efforts toward the development of low-molecular-weight pharmaceuticals that directly block the detrimental actions of TNF and RANKL.
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http://dx.doi.org/10.2174/1568026618666180607084430DOI Listing
August 2018

Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis.

Proc Natl Acad Sci U S A 2018 06 29;115(24):E5546-E5555. Epub 2018 May 29.

Department of Immunology, Biomedical Sciences Research Centre "Alexander Fleming," 16672 Vari, Greece;

Mesenchymal cells in the microenvironment of cancer exert important functions in tumorigenesis; however, little is known of intrinsic pathways that mediate these effects. MAPK signals, such as from MAPKAPK2 (MK2) are known to modulate tumorigenesis, yet their cell-specific role has not been determined. Here, we studied the cell-specific role of MK2 in intestinal carcinogenesis using complete and conditional ablation of MK2. We show that both genetic and chemical inhibition of MK2 led to decreased epithelial cell proliferation, associated with reduced tumor growth and invasive potential in the mouse model. Notably, this function of MK2 was not mediated by its well-described immunomodulatory role in immune cells. Deletion of MK2 in intestinal mesenchymal cells (IMCs) led to both reduced tumor multiplicity and growth. Mechanistically, MK2 in IMCs was required for Hsp27 phosphorylation and the production of downstream tumorigenic effector molecules, dominantly affecting epithelial proliferation, apoptosis, and angiogenesis. Genetic ablation of MK2 in intestinal epithelial or endothelial cells was less effective in comparison with its complete deletion, leading to reduction of tumor size via modulation of epithelial apoptosis and angiogenesis-associated proliferation, respectively. Similar results were obtained in a model of colitis-associated carcinogenesis, indicating a mesenchymal-specific role for MK2 also in this model. Our findings demonstrate the central pathogenic role of mesenchymal-specific MK2/Hsp27 axis in tumorigenesis and highlight the value of mesenchymal MK2 inhibition in the treatment of cancer.
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http://dx.doi.org/10.1073/pnas.1805683115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004446PMC
June 2018

Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis.

JCI Insight 2018 04 5;3(7). Epub 2018 Apr 5.

Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.

Mesenchymal TNF signaling is etiopathogenic for inflammatory diseases such as rheumatoid arthritis and spondyloarthritis (SpA). The role of Tnfr1 in arthritis has been documented; however, Tnfr2 functions are unknown. Here, we investigate the mesenchymal-specific role of Tnfr2 in the TnfΔARE mouse model of SpA in arthritis and heart valve stenosis comorbidity by cell-specific, Col6a1-cre-driven gene targeting. We find that TNF/Tnfr2 signaling in resident synovial fibroblasts (SFs) and valvular interstitial cells (VICs) is detrimental for both pathologies, pointing to common cellular mechanisms. In contrast, systemic Tnfr2 provides protective signaling, since its complete deletion leads to severe deterioration of both pathologies. SFs and VICs lacking Tnfr2 fail to acquire pathogenic activated phenotypes and display increased expression of antiinflammatory cytokines associated with decreased Akt signaling. Comparative RNA sequencing experiments showed that the majority of the deregulated pathways in TnfΔARE mesenchymal-origin SFs and VICs, including proliferation, inflammation, migration, and disease-specific genes, are regulated by Tnfr2; thus, in its absence, they are maintained in a quiescent nonpathogenic state. Our data indicate a pleiotropy of Tnfr2 functions, with mesenchymal Tnfr2 driving cell activation and arthritis/valve stenosis pathogenesis only in the presence of systemic Tnfr2, whereas nonmesenchymal Tnfr2 overcomes this function, providing protective signals and, thus, containing both pathologies.
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http://dx.doi.org/10.1172/jci.insight.98864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928856PMC
April 2018

Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis.

Ann Rheum Dis 2018 06 23;77(6):926-934. Epub 2018 Feb 23.

Institute of Immunology, Biomedical Sciences Research Center (BSRC), 'Alexander Fleming', Vari, Greece.

Objectives: Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities.

Methods: Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the transgene. Tg197 and Tg197 mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis.

Results: Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative -expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype o, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities.

Conclusions: Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.
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http://dx.doi.org/10.1136/annrheumdis-2017-212597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965351PMC
June 2018