Antonio González

Instituto de Investigación Sanitaria de Santiago

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Juan J. Gómez‐Reino

Hospital Clínico Universitario de Valencia

103

Eva Pérez‐Pampín

Complejo Hospitalario Universitario de Santiago

Francisco J. Blanco

Complexo Hospitalario Universitario A Coruña

Manuel Calaza

Universidade de Santiago de Compostela

ÁG

Ángel G. Ravelo

Universidad de La Laguna

Rob Knight

University of California, San Diego

John Loughlin

Newcastle University

Braulio M. Fraga

Instituto de Productos Naturales y Agrobiología

Antonio Mera

Universidade de Santiago de Compostela

Alejandro Balsa

Hospital Universitario La Paz

Cooperative Institutions

Universidad de La Laguna

192

University of California, San Diego

177

Consejo Superior de Investigaciones Científicas

148

Harvard University

126

Center for Rheumatology

114

Instituto de Productos Naturales y Agrobiología

102

Center for Autism and Related Disorders

National Institutes of Health

Instituto de Salud Carlos III

Simons Foundation

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THU0062 Wnt5a involvement in migration, invasion and the pro-inflammatory phenotype of rheumatoid synoviocytes

Annals of the Rheumatic Diseases (2018)

Ángela Rodríguez-Trillo Nerea Mosquera Antonio Mera Antonio González Carmen Conde

Background

Fibroblast-like synoviocytes (FLS) are pivotal in the inflammation and joint damage of rheumatoid arthritis (RA). These cells acquire an aggressive phenotype; they migrate and invade articular structures perpetuating synovial inflammation. Also, they contribute to cartilage and bone damage by secretion of cytokines, metalloproteinases and cathepsins. The mechanisms modulating migration and invasion of FLS are not yet completely known. Recently, the role of the non-canonical pathway of Wnt5a has been highlighted in these processes, as well as, its contribution to osteoclastogenesis. Moreover, Wnt5a could be involved in other pathogenic aspects of RA, as suggested by its involvement in tissue inflammation through regulation of cytokine, chemokine and metalloprotease expression. Thus, the study of the non-canonical pathway of Wnt5a in the aggressive phenotype of FLS and the inflammatory response may provide new therapeutic targets for the RA.

Objectives

To analyse the involvement of Wnt5a in the proliferation, migration, invasion and inflammatory responses of FLS from RA patients.

Methods

FLS were obtained from eight RA patients. Expression of Wnt5a was suppressed by siRNA transfection (Dharmacon). Cellular proliferation was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). Migration was analysed by the wound-healing assay using Ibidi inserts. The occupation area was determined by Image J. Invasion was tested by quantifying Giemsa stained cells on the bottom side of Matrigel coated trans-membrane (Millipore). The expression of inflammatory mediators and metalloproteases was analysed by real-time PCR after stimulation with recombinant Wnt5a protein (rWnt5a), TNF and combined treatment.

Results

We analysed the effect of the absence of Wnt5a and rWnt5a on the proliferation, migration and invasion of RA FLS. FLS lacking Wnt5a showed a significant migration decrease, 27.9% in basal condition and 16.9% after TNF stimulation, when compared with FLS transfected with siRNA control. Accordingly, migration of RA FLS treated with rWnt5a was increased by 48.5% when compared with cells treated with the vehicle. No change in migration was observed in TNF-stimulated FLS. Invasive capacity was reduced, reaching 71.4% of that observed in FLS transfected with siRNA control in basal conditions. In addition, invasion in FLS treated with rWnt5a was 35.7% higher than in controls. We also analysed the effect of rWnt5a on the inflammatory response of RA FLS. We found a significantly increase of IL6, IL8, CCL2, CXCL5, MMP9 and MMP13 basal expression and the TNF-induced expression of IL6, IL8, CXCL5 and MMP3. Nevertheless, the lack of Wnt5a or the addition of rWnt5a did not modify the spontaneous or the TNF-induced proliferation.

Conclusions

These results indicate that Wnt5a contributes to the aggressive phenotype of FLS by potentiating their migration and invasion, and by stimulating the inflammatory response.

Acknowledgements

Supported by grant of the ISCIII/PI14/01660/RETICS Program, RD16/0012/0014/cofinanced FEDER.

Disclosure of Interest

None declared

WNT5A

Matrigel

Proinflammatory cytokine

10.1136/annrheumdis-2018-eular.4538

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Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility.

PubMed (2020)

Aurélie De Groof Jean‐Pierre Pignon Laura Vidal-Bralo Donatienne Tyteca Christine Galant

TLR3 mediates skin solar injury by binding nuclear material released from apoptotic keratinocytes, resulting in the production of pro-inflammatory cytokines. Because the TLR3 gene is located in 4q35, a known systemic lupus erythematosus (SLE) susceptibility locus, we wondered whether TLR3 single nucleotide polymorphisms (SNPs) were associated with inflammatory mechanisms relevant to the development of SLE, and disease susceptibility.Functional assays were carried out in TLR3-transfected HEK293 cells and in monocyte-derived dendritic cells (moDCs). TLR3 and IFNβ immunofluorescence studies were performed in skin samples from 7 SLE patients and 3 controls. We performed a SNP association study in a discovery cohort of 153 patients and 105 controls, followed by a confirmation study in an independent cohort of 1,380 patients and 2,104 controls.TLR3 and IFNβ are overexpressed in SLE skin lesions. TLR3 overexpression in HEK293 cells amplifies their sensitivity to a pro-apoptotic stimulus. Taking advantage of a naturally occurring polymorphic TLR3 variant (rs3775291) that weakly versus strongly responds to poly I:C stimulation, we found that TLR3 is associated with amplified apoptotic responses, production of the Ro/SSA autoantigen and increased maturation of myeloid-derived dendritic cells (moDC) after exposure to UV irradiation. However, TLR3 SNPs are not associated with susceptibility to SLE in a large population of patients and controls.TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease.

TLR7

TLR3

Source

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83 ANALYSIS OF CANDIDATE OSTEOARTHRITIS GENES IN A META-ANALYSIS OF 8 GENOME-WIDE ASSOCIATION STUDIES

Osteoarthritis and Cartilage (2011)

C. Rodriguez-Fontela Εvangelos Εvangelou Ana M. Valdes Manuel Calaza Nigel Arden

Genome-wide Association Study

Candidate gene

Genetic Association

10.1016/s1063-4584(11)60110-6

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Association of a non-synonymous single-nucleotide polymorphism of DNASEI with SLE susceptibility

Lara D. Veeken (2006)

Ana Bodaño Antonio González Isabel Ferreirós-Vidal Eva Balada Jaume Ordï

Objectives. To investigate the association of a non-synonymous single-nucleotide polymorphism (SNP) in DNASEI with susceptibility to systemic lupus erythematosus (SLE) and the production of autoantibodies to nuclear antigens.

10.1093/rheumatology/kel019

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Citations (55)

New ent-pimarane diterpenes

Tetrahedron (1990)

Antonio González José J. Mendoza Javier G. Luis Ángel G. Ravelo Teresa A. Grillo

Absolute Configuration

Spectral Analysis

Derivative (finance)

Vibrational Circular Dichroism

10.1016/s0040-4020(01)89760-x

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Citations (2)

ChemInform Abstract: PARTIAL SYNTHESIS OF A TRACHYLOBAGIBBERELLIN ANALOG

Chemischer Informationsdienst (1985)

Jacinto D. Arraez Braulio M. Fraga Antonio González J. G. LUIS J. Fayos

Abstract Das Trachynodiol (I) wird in das Lacton (IVb) übergeführt [aus dem als Nebenprodukt auftretenden Lactol (V) kann (IVa) wieder durch Oxidation regeneriert werden].

Lactol

10.1002/chin.198523310

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Anti-tumor promoting effects of sesquiterpenes from Maytenus cuzcoina (celastraceae)

Bioorganic & Medicinal Chemistry (2000)

Antonio González Benigna M. Tincusi Isabel L. Bazzocchi Harukuni Tokuda Hoyoku Nishino

Celastraceae

Heteronuclear molecule

Structure–activity relationship

10.1016/s0968-0896(00)00107-3

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Citations (46)

QIIME 2: Reproducible, interactive, scalable, and extensible microbiome data science

Evan Bolyen Jai Ram Rideout Matthew R. Dillon Nicholas A. Bokulich Christian C. Abnet

We present QIIME 2, an open-source microbiome data science platform accessible to users spanning the microbiome research ecosystem, from scientists and engineers to clinicians and policy makers. QIIME 2 provides new features that will drive the next generation of microbiome research. These include interactive spatial and temporal analysis and visualization tools, support for metabolomics and shotgun metagenomics analysis, and automated data provenance tracking to ensure reproducible, transparent microbiome data science.

10.7287/peerj.preprints.27295v1

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Citations (632)

Modeling brain-dedicated PET systems using metascintillators for optimized ToF capability

Daniel Alexandre Baptista Bonifácio Riccardo Latella Helio Massaharu Murata J. Benlloch Antonio González

Recent trends in Positron Emission Tomography (PET) use the time-of-flight (ToF) information in the image reconstruction process to improve the signal-to-noise ratio and the positioning of the annihilation event. One of the components that most contributes to the accuracy of the ToF-PET is the scintillation crystal. The metascintillator approach has been proposed to overcome the time resolution limits of commonly used scintillators. The metascintillator is an engineered composition of small units that combines and optimizes several features in a single scintillator heterostructure. In this work, metascintillator-based brain PET systems were modeled using the GATE Monte Carlo toolkit and compared with designs based on bulk LYSO or BGO. Sensitivity, noise equivalent count rate and scatter fraction were evaluated following the NEMA guidelines. Only data in the list mode format was used for comparison purposes to avoid dependence on the image reconstruction algorithm. To achieve the same peak sensitivity of a system based on a 15 mm thick bulk BGO, the metascintillator-based scanners using BGO/BaF2 , BGO/EJ232, LYSO/BaF2 and LYSO/EJ232 must have thicknesses of 23.2 mm, 22.5 mm, 29.7 mm and 31.1 mm, respectively. The objective of this work is to determine the clinical value of using metascintillator-based detectors in brain PET.

Lyso-

Positron emission

Silicon Photomultiplier

10.36227/techrxiv.23699694.v1

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Citations (1)

ChemInform Abstract: MARINE NATURAL PRODUCTS FROM THE ATLANTIC ZONE. PART 25. NONTERPENOID C-15 METABOLITES FROM THE RED SEAWEED LAURENCIA PINNATIFIDA

Chemischer Informationsdienst (1982)

Antonio González Julio D. Martı́n Victor S. Martı́n Manuel Norte R. Pérez

Abstract Aus der Rotalge Laurencia pinnatifida werden cis‐Pinnatifidenin (I), das trans‐Isomere (II) und das acyclische Trienin (III) isoliert.

Laurencia

10.1002/chin.198237340

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Citations (2)