المؤلفون: Alessandra Nerviani, Marie-Astrid Boutet, Giulia Maria Ghirardi, Katriona Goldmann, Elisabetta Sciacca, Felice Rivellese, Elena Pontarini, Edoardo Prediletto, Federico Abatecola, Mattia Caliste, Sara Pagani, Daniele Mauro, Mattia Bellan, Cankut Cubuk, Rachel Lau, Sarah E. Church, Briana M. Hudson, Frances Humby, Michele Bombardieri, Myles J. Lewis, Costantino Pitzalis

المصدر: Nature Communications, Vol 15, Iss 1, Pp 1-16 (2024)

مصطلحات موضوعية: Science

الوصف: Abstract The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/479b8ed47d1c4eb09e9de80de7cc33efTest

المؤلفون: Anais Defois, Nina Bon, Alexandre Charpentier, Melina Georget, Nicolas Gaigeard, Frederic Blanchard, Antoine Hamel, Denis Waast, Jean Armengaud, Ophelie Renoult, Claire Pecqueur, Yves Maugars, Marie-Astrid Boutet, Jerome Guicheux, Claire Vinatier

المصدر: Cell Communication and Signaling, Vol 21, Iss 1, Pp 1-18 (2023)

مصطلحات موضوعية: Metabolism, Inflammation, Osteoarthritis, Chondrocytes, Medicine, Cytology, QH573-671

الوصف: Abstract Background Osteoarthritis is an age-related disease that currently faces a lack of symptomatic treatment. Inflammation, which is mainly sustained by pro-inflammatory cytokines such as IL-1b, TNF, and IL-6, plays an important role in osteoarthritis progression. In this context, pro-inflammatory cytokines are widely used to mimic the inflammatory component of osteoarthritis in vitro. However, the therapeutic failures of clinical trials evaluating anti-cytokines drugs highlight the lack of overall understanding of the effects of these cytokines on chondrocytes. Methods Here, we generated a comprehensive transcriptomic and proteomic dataset of osteoarthritic chondrocytes treated with these cytokines to describe their pro-inflammatory signature and compare it to the transcriptome of non-osteoarthritic chondrocytes. Then, the dysregulations highlighted at the molecular level were functionally confirmed by real-time cellular metabolic assays. Results We identified dysregulation of metabolic-related genes in osteoarthritic chondrocytes but not in non-osteoarthritic chondrocytes. A metabolic shift, toward increased glycolysis at the expense of mitochondrial respiration, was specifically confirmed in osteoarthritic chondrocytes treated with IL-1b or TNF. Conclusion These data show a strong and specific association between inflammation and metabolism in osteoarthritic chondrocytes, which was not found in non-osteoarthritic chondrocytes. This indicates that the link between inflammation and metabolic dysregulation may be exacerbated during chondrocyte damage in osteoarthritis. Video Abstract

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1478-811XTest

الوصول الحر: https://doaj.org/article/7a3c0f5b50e040b1ac7c119af7ea7643Test

المؤلفون: Marie-Astrid Boutet, Alessandra Nerviani, Gloria Lliso-Ribera, Roberto Leone, Marina Sironi, Rebecca Hands, Felice Rivellese, Annalisa Del Prete, Katriona Goldmann, Myles J. Lewis, Alberto Mantovani, Barbara Bottazzi, Costantino Pitzalis

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: pentraxin-3, rheumatoid arthritis, synovial tissue, pathotypes, inflammation, Immunologic diseases. Allergy, RC581-607

الوصف: AimsTo determine the relationship between PTX3 systemic and synovial levels and the clinical features of rheumatoid arthritis (RA) in a cohort of early, treatment naïve patients and to explore the relevance of PTX3 expression in predicting response to conventional-synthetic (cs) Disease-Modifying-Anti-Rheumatic-Drugs (DMARDs) treatment.MethodsPTX3 expression was analyzed in 119 baseline serum samples from early naïve RA patients, 95 paired samples obtained 6-months following the initiation of cs-DMARDs treatment and 43 healthy donors. RNA-sequencing analysis and immunohistochemistry for PTX3 were performed on a subpopulation of 79 and 58 synovial samples, respectively, to assess PTX3 gene and protein expression. Immunofluorescence staining was performed to characterize PTX3 expressing cells within the synovium.ResultsCirculating levels of PTX3 were significantly higher in early RA compared to healthy donors and correlated with disease activity at baseline and with the degree of structural damages at 12-months. Six-months after commencing cs-DMARDs, a high level of PTX3, proportional to the baseline value, was still detectable in the serum of patients, regardless of their response status. RNA-seq analysis confirmed that synovial transcript levels of PTX3 correlated with disease activity and the presence of mediators of inflammation, tissue remodeling and bone destruction at baseline. PTX3 expression in the synovium was strongly linked to the degree of immune cell infiltration, the presence of ectopic lymphoid structures and seropositivity for autoantibodies. Accordingly, PTX3 was found to be expressed by numerous synovial cell types such as plasma cells, fibroblasts, vascular and lymphatic endothelial cells, macrophages, and neutrophils. The percentage of PTX3-positive synovial cells, although significantly reduced at 6-months post-treatment as a result of global decreased cellularity, was similar in cs-DMARDs responders and non-responders.ConclusionThis study demonstrates that, early in the disease and prior to treatment modification, the level of circulating PTX3 is a reliable marker of RA activity and predicts a high degree of structural damages at 12-months. In the joint, PTX3 associates with immune cell infiltration and the presence of ectopic lymphoid structures. High synovial and peripheral blood levels of PTX3 are associated with chronic inflammation characteristic of RA. Additional studies to determine the mechanistic link are required.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.686795/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/adf6570f157f4641b27a9d7a4553cc17Test

المؤلفون: Alessandra Nerviani, Maria Di Cicco, Arti Mahto, Gloria Lliso-Ribera, Felice Rivellese, Georgina Thorborn, Rebecca Hands, Mattia Bellan, Daniele Mauro, Marie-Astrid Boutet, Giovanni Giorli, Myles Lewis, Stephen Kelly, Michele Bombardieri, Frances Humby, Costantino Pitzalis

المصدر: Frontiers in Immunology, Vol 11 (2020)

مصطلحات موضوعية: synovial tissue, anti-TNF, pathotype, rheumatoid arthritis, certolizumab-pegol, Immunologic diseases. Allergy, RC581-607

الوصف: Objectives: To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment.Methods: Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust and underwent synovial sampling of an actively inflamed joint using ultrasound-guided needle biopsy before commencing certolizumab-pegol and after 12-weeks. At 12-weeks, patients were categorized as responders if they had a DAS28 fall >1.2. A minimum of 6 samples was collected for histological analysis. Based on H&E and immunohistochemistry (IHC) staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages) patients were categorized into three distinct synovial pathotypes (lympho-myeloid, diffuse-myeloid, and pauci-immune).Results: At baseline, as per inclusion criteria, DAS28 mean was 6.4 ± 0.9. 94.6% of the synovial tissue was retrieved from the wrist or a metacarpophalangeal joint. Histological pathotypes were distributed as follows: 58% lympho-myeloid, 19.4% diffuse-myeloid, and 22.6% pauci-immune. Patients with a pauci-immune pathotype had lower levels of CRP but higher VAS fatigue compared to lympho- and diffuse-myeloid. Based on DAS28 fall >1.2, 67.6% of patients were deemed as responders and 32.4% as non-responders. However, by categorizing patients according to the baseline synovial pathotype, we demonstrated that a significantly higher number of patients with a lympho-myeloid and diffuse-myeloid pathotype in comparison with pauci-immune pathotype [83.3% (15/18), 83.3 % (5/6) vs. 28.6% (2/7), p = 0.022) achieved clinical response to certolizumab-pegol. Furthermore, we observed a significantly higher level of post-treatment tender joint count and VAS scores for pain, fatigue and global health in pauci-immune in comparison with lympho- and diffuse-myeloid patients but no differences in the number of swollen joints, ESR and CRP. Finally, we confirmed a significant fall in the number of CD68+ sublining macrophages post-treatment in responders and a correlation between the reduction in the CD20+ B-cells score and the improvement in the DAS28 at 12-weeks.Conclusions: The analysis of the synovial histopathology may be a helpful tool to identify among clinically indistinguishable patients those with lower probability of response to TNFα-blockade.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fimmu.2020.00845/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/a8f3e6023d28418f98107e55997c782fTest

المؤلفون: Marie-Astrid Boutet, Alessandra Nerviani, Costantino Pitzalis

المصدر: International Journal of Molecular Sciences, Vol 20, Iss 6, p 1257 (2019)

مصطلحات موضوعية: psoriasis, psoriatic arthritis, rheumatoid arthritis, interleukin-36, interleukine-1, interleukin-37, interleukin-38, TLR, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: The interleukin (IL)-1 family of cytokines is composed of 11 members, including the most recently discovered IL-36α, β, γ, IL-37, and IL-38. Similar to IL-1, IL-36 cytokines are initiators and amplifiers of inflammation, whereas both IL-37 and IL-38 display anti-inflammatory activities. A few studies have outlined the role played by these cytokines in several inflammatory diseases. For instance, IL-36 agonists seem to be relevant for the pathogenesis of skin psoriasis whereas, despite being expressed within the synovial tissue, their silencing or overexpression do not critically influence the course of arthritis in mice. In this review, we will focus on the state of the art of the molecular features and biological roles of IL-36, IL-37, and IL-38 in representative skin- and joint-related inflammatory diseases, namely psoriasis, rheumatoid arthritis, and psoriatic arthritis. We will then offer an overview of the therapeutic potential of targeting the IL-36 axis in these diseases, either by blocking the proinflammatory agonists or enhancing the physiologic inhibitory feedback on the inflammation mediated by the antagonists IL-37 and IL-38.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/1422-0067/20/6/1257Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/73436bd43b7c4af7a8729d1ba22c29b3Test

المؤلفون: Marie-Astrid Boutet, Alessandra Nerviani, Gabriele Gallo Afflitto, Costantino Pitzalis

المصدر: International Journal of Molecular Sciences, Vol 19, Iss 2, p 530 (2018)

مصطلحات موضوعية: psoriasis, psoriatic arthritis, interleukin-17, interleukine-23, Th17 cells, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Psoriasis is a chronic systemic inflammatory disease causing erythematosus and scaly skin plaques; up to 30% of patients with psoriasis develop Psoriatic Arthritis (PsA), which is characterised by inflammation and progressive damage of the peripheral joints and/or the spine and/or the entheses. The pathogenic mechanisms driving the skin disorder in psoriasis and the joint disease in PsA are sustained by the activation of inflammatory pathways that can be overlapping, but also, at least partially, distinct. Cytokines members of the IL-23/IL-17 family, critical in the development of autoimmunity, are abundantly expressed within the cutaneous lesions but also seem to be involved in chronic inflammation and damage of the synovium though, as it will be here discussed, not in all patients. In this review, we will focus on the state of the art of the molecular features of psoriatic skin and joints, focusing on the specific role of the IL-23/IL-17 pathway in each of these anatomical districts. We will then offer an overview of the approved and in-development biologics targeting this axis, emphasising how the availability of the “target” in the diseased tissues could provide a plausible explanation for the heterogeneous clinical efficacy of these drugs, thus opening future perspective of personalised therapies.

وصف الملف: electronic resource

العلاقة: http://www.mdpi.com/1422-0067/19/2/530Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/f5dc70d4ee154a38b93027ea6c1e728dTest

المؤلفون: Christelle Darrieutort-Laffite, Marie-Astrid Boutet, Mathias Chatelais, Régis Brion, Frédéric Blanchard, Dominique Heymann, Benoit Le Goff

المصدر: Mediators of Inflammation, Vol 2014 (2014)

مصطلحات موضوعية: Pathology, RB1-214

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/0962-9351Test; https://doaj.org/toc/1466-1861Test

الوصول الحر: https://doaj.org/article/9e36fab9d15c42f3bc21b2580a2d08aeTest

المؤلفون: Nicolas Gaigeard, Frédéric Blanchard, Claire Vinatier, Benoit Le Goff, Jérôme Guicheux, Marie-Astrid Boutet

المصدر: Revue du Rhumatisme. 90:305-312

مصطلحات موضوعية: Rheumatology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::0f59519c519f8141995bb23b0035f527Test
https://doi.org/10.1016/j.rhum.2022.12.015Test

المؤلفون: Nirupam Purkayastha, Myles Lewis, Katriona Goldmann, W.S. Tan, Alessandra Nerviani, Stephen Kelly, Marie-Astrid Boutet, Tamás Lajtos, Costantino Pitzalis, Rebecca Hands

المصدر: Annals of the Rheumatic Diseases

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Psoriatic Arthritis, Immunology, Arthritis, Interleukin-23, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Rheumatology, Synovitis, Ustekinumab, medicine, Interleukin 23, Humans, Immunology and Allergy, Skin, 030203 arthritis & rheumatology, Principal Component Analysis, Molecular pathology, business.industry, Gene Expression Profiling, Arthritis, Psoriatic, Interleukin-17, Synovial Membrane, Interleukin, Middle Aged, medicine.disease, Treatment Outcome, 030104 developmental biology, arthritis, biological therapy, Antirheumatic Agents, Immunohistochemistry, Female, Tumor Necrosis Factor Inhibitors, psoriatic, business, medicine.drug

الوصف: ObjectivesTo determine the relationship between synovial versus skin transcriptional/histological profiles in patients with active psoriatic arthritis (PsA) and explore mechanistic links between diseased tissue pathology and clinical outcomes.MethodsTwenty-seven active PsA patients were enrolled in an observational/open-label study and underwent biopsies of synovium and paired lesional/non-lesional skin before starting anti-tumour necrosis factor (TNF) (if biologic-naïve) or ustekinumab (if anti-TNF inadequate responders). Molecular analysis of 80-inflammation-related genes and protein levels for interleukin (IL)-23p40/IL-23p19/IL-23R were assessed by real-time-PCR and immunohistochemistry, respectively.ResultsAt baseline, all patients had persistent active disease as per inclusion criteria. At primary end-point (16-weeks post-treatment), skin responses favoured ustekinumab, while joint responses favoured anti-TNF therapies. Principal component analysis revealed distinct clustering of synovial tissue gene expression away from the matched skin. While IL12B, IL23A and IL23R were homogeneously expressed in lesional skin, their expression was extremely heterogeneous in paired synovial tissues. Here, IL-23 transcriptomic/protein expression was strongly linked to patients with high-grade synovitis who, however, were not distinguishable by conventional clinimetric measures.ConclusionsPsA synovial tissue shows a heterogeneous IL-23 axis profile when compared with matched skin. Synovial molecular pathology may help to identify among clinically indistinguishable patients those with a greater probability of responding to IL-23 inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b6a9eb1d14d750c870bd378942d36860Test
https://doi.org/10.1136/annrheumdis-2020-218186Test

المؤلفون: Myles Lewis, Katriona Goldmann, Costantino Pitzalis, Gloria Lliso-Ribera, Edoardo Prediletto, Giulia Maria Ghirardi, Alessandra Nerviani, Marie-Astrid Boutet, Davide Lucchesi

المصدر: Rheumatology (Oxford, England)

مصطلحات موضوعية: rheumatoid arthritis, musculoskeletal diseases, 0301 basic medicine, Oncology, medicine.medical_specialty, Biopsy, medicine.medical_treatment, Gene Expression, Arthritis, interleukin-36, In Vitro Techniques, urologic and male genital diseases, early arthritis, Arthritis, Rheumatoid, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Rheumatology, Psoriasis, Synovitis, Internal medicine, Humans, Medicine, Pharmacology (medical), RNA, Messenger, skin and connective tissue diseases, psoriatic arthritis, Inflammation, 030203 arthritis & rheumatology, business.industry, Interleukins, Arthritis, Psoriatic, Synovial Membrane, Clinical Science, medicine.disease, Synoviocytes, cytokines, Prostate-specific antigen, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Antirheumatic Agents, Rheumatoid arthritis, Synovial membrane, synovitis, business, Interleukin-1

الوصف: Objectives IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy. Methods Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes. Results PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts. Conclusion The impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa1547103aec23bfdbf70775b76667cfTest
https://doi.org/10.1093/rheumatology/kez358Test