Non-canonical (non-SMAD2/3) TGF-β signaling in fibrosis: Mechanisms and targets

Pulmonary hypertension (PH) is a frequent and severe complication of systemic sclerosis (SSc). PH in SSc is highly heterogeneous because of the various clinical phenotypes of SSc itself and because the mechanisms of PH can vary from one patient to another. PH in SSc may be due to vasculopathy of the small pulmonary arteries (group 1; pulmonary arterial hypertension), interstitial lung disease (group 3; PH due to lung disease or chronic hypoxia) or myocardial fibrosis leading to left ventricular systolic or diastolic dysfunction (group 2; PH due to chronic left-heart disease). Pulmonary veno-occlusive disease is not uncommon in SSc and may also cause PH in some patients (group 1'). There is a high prevalence of each of these conditions in SSc and, as such, it may be difficult to determine the dominant cause of PH in a particular patient. However, careful phenotyping of PH in SSc is important as the therapy required for each of these underlying conditions is very different. In this review, we will decipher the different phenotypes of SSc-PH.

https://err.ersjournals.com/content/errev/26/145/170056.full.pdf

Pulmonary hypertension in systemic sclerosis: different phenotypes

Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic non-healing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing.In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies.Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulc...

https://www.tandfonline.com/doi/pdf/10.1080/15476278.2015.1126018

Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds.

Systemic sclerosis (SSc) is an autoimmune disease characterized by an aberrant immune system response, progressive fibrosis and microvasculature damage that affects organs and systems including skin, lungs, heart, digestive system, kidneys, muscles, joints, and nervous system. Several factors, including genetic and environmental, are involved in the SSc pathogenesis by leading to a pathological autoimmune response, exacerbated extracellular deposition and abnormal vascular restructuring. SSc-associated fibrosis and vascular damage can be caused by the altered secretion of growth factor and profibrotic cytokines, including transforming growth factor-beta (TGF-beta), interleukin-4 (IL-4), platelet-derived growth factor (PDGF), and connective-tissue growth factor. Such massive inflammatory response activates different biological events, including endothelial cells phenotypic conversion into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndMT. Among the multitude of proinflammatory factors involved in SSs-associated fibrosis and vascular derangement, reactive oxygen species (ROS) are paramount effectors. In this context, ROS-induced oxidative stress has been found implicated in mediating and/or activating TGF-β -induced EndMT in various diseases molecular models, suggesting the idea that a similar mechanism can be potentially involved in SSc. In this review, we collected and critically analyzed all the PubMed's articles providing experimental correlations between increased ROS generation and EndMT, as well as of the presence of the EndMT process in SSc, highlighting a potential link between oxidative stress and EndMT in this disease.

/pdf/a-potential-link-between-oxidative-stress-and-endothelial-to-4ywm0dd1yq.pdf

A Potential Link Between Oxidative Stress and Endothelial-to-Mesenchymal Transition in Systemic Sclerosis.

Career situation of first and presenting author Student for a master or a PhD Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting Immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases.1 Tfh cells can infiltrate the skin of SSc patients, and induce fibrosis in vitro.2 Objectives The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc. Methods Using flow cytometry, we analyzed cTfh cells from 52 SSc patients with no immodulotary treatment and 38 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells from 13 SSc patients and 6 HC were performed for functional analysis. IgG and IgM production were measured by ELISA. BCL-6, Blimp-1, CXCL13 and IL-21 expression were analyzed by RTqPCR. Results We observed that cTfh cell numbers are increased in SSc patients compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from SSc patients present an activated Tfh phenotype, with high expression of BCL-6 and increased capacity to produce IL-21 in comparison to HC. In vitro, cTfh cells from SSc patients had higher capacity to stimulate the differentiation of CD19+CD27+CD38hi B cells and their secretion of IgG and IgM through the IL-21 pathway than cTfh cells from HC. Blocking IL-21 or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells9 capacity to stimulate the plasmablasts and Ig production. Conclusions Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc. References Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014;41(4):529-42. Taylor DK, Mittereder N, Kuta E, Delaney T, Burwell T, Dacosta K, et al. T follicular helper-like cells contribute to skin fibrosis. Sci Transl Med 2018;10(431). Acknowledgements This work was supported by the Aterhit foundation and received grants from 9Groupe Francophone de Recherche sur la Sclerodermie’ (GFRS). Disclosure of Interest None declared

https://ard.bmj.com/content/annrheumdis/early/2019/02/12/annrheumdis-2018-214382.full.pdf

Circulating follicular helper T cells are increased in systemic sclerosis and promote plasmablast differentiation through the IL-21 pathway which can be inhibited by ruxolitinib

Major work has been done in order to improve the understanding of systemic sclerosis (SSc) pathogenesis. A number of new experimental models have been set up, that should help to understand the disease pathogenesis and test new therapeutic targets. Reactive oxygen species represent a hallmark of the pathogenesis of SSc, both at the fibroblast and at the endothelial cell levels. Although a large number of genetic studies have been conducted, it is still difficult to identify a genetic background specific to SSc, and the major progress in this setting is probably the identification of an interferon signature. Besides endothelial cells and fibroblasts, major development has been made in the understanding of the role of B cells and autoantibodies in the pathogenesis of SSc. Plasmacytoid dendritic cells seem to play a major role in the pathogenesis of SSc through the secretion of CXCL4, although these data will need to be confirmed in the near future.

Pathophysiology of systemic sclerosis: state of the art in 2014.

Purpose Systemic sclerosis (SSc) is characterized by autoimmunity, vasculopathy and fibrosis. Fibrosis is due to an activation of fibroblasts by the transforming growth factor-s (TGF-s). This study investigates the proteomic response of SSc fibroblasts to TGF-s. Experimental design Skin fibroblasts from diffuse SSc patients and healthy controls (HC) are cultured with or without TGF-s. Two-dimensional differential in-gel electrophoresis and mass spectrometry (MS) combined with Ingenuity Pathway analysis (IPA) and Panther/David software analyze proteins differentially expressed between groups. Real-time cell analyzer (RTCA) assesses fibroblast proliferation and viability. Results Two-hundred-and-seventy-nine proteins are differentially expressed between groups. Principal component analysis shows significant differences between groups. IPA shows specific process networks such as actin cytoskeleton and integrin signaling. Panther and David software show predominant biological processes such as cellular and metabolic processes. TGF-s enhances protein synthesis and protein pathways. IPA and RTCA suggest the involvement of epidermal growth factor receptor (EGFR) and phosphatidylinositol 3 kinase (Pi3K). Conclusions and clinical relevance That the proteome of fibroblasts differs between SSc patients and HC is confirmed, and it is demonstrated that fibroblasts exacerbate their proteomic phenotype upon stimulation with TGF-s. EGFR and Pi3K are highlighted as proteins of interest in SSc fibroblasts.

/pdf/proteomic-analysis-of-human-scleroderma-fibroblasts-response-1nfqfwier0.pdf

Proteomic Analysis of Human Scleroderma Fibroblasts Response to Transforming Growth Factor-ß.

Introduction La granulomatose eosinophilique avec polyangeite est une vascularite associee aux anticorps anticytoplasme des polynucleaires neutrophiles (ANCA) caracterisee par un asthme severe a debut tardif, une hypereosinophilie sanguine et des manifestations systemiques liees a une vascularite et a une infiltration tissulaire par les eosinophiles. Les etudes physiopathologiques sont rares, expliquant en partie l’absence de strategies therapeutiques ciblees. Nous avons etudie les profils d’activation lymphocytaires T et B, les cellules de l’immunite innee de type 2 (ILC2) ainsi que les differentes cytokines pouvant jouer un role dans la physiopathologie de la maladie. Patients et methodes Les sous-populations lymphocytaires B, T et ILC2 ont ete etudiees par cytometrie en flux dans le sang peripherique de patients avec une granulomatose eosinophilique avec polyangeite active (n = 14), en remission (n = 8) ainsi que chez des sujets sains (n = 20). Les principales cytokines associees a ces sous-populations lymphocytaires ont ete dosees dans le serum de patients avec une granulomatose eosinophilique avec polyangeite active (n = 20), en remission (n = 25) et de sujets sains (n = 35) par Elisa et Luminex. Resultats L’etude des sous-populations lymphocytaires montrait chez les malades, comparativement aux sujets sains, une augmentation significative des lymphocytes T CD4+ de type TH2 (3,6 ± 3,8 % contre 1,1 ± 1,3 % p = 0,002) et une augmentation non significative des lymphocytes TH9 (0,81 ± 0,86 % contre 0,40 ±  0,52 %, p = 0,1) et TH17 (1,5 ± 1,1 % contre 0,9 ± 0,5 % p = 0,052). Les lymphocytes T helper folliculaires (TFH) etaient augmentes chez les malades (7,3 ± 3,1 % contre 4,5 ± 1,5 % p = 0,001), tandis que les lymphocytes T regulateurs etaient diminues (0,75 ± 0,4 % contre 1,5 ± 0,8 p = 0,02). Les lymphocytes B des malades atteints de granulomatose eosinophilique avec polyangeite avaient un profil active comparativement aux lymphocytes B de sujets sains, avec une augmentation significative des marqueurs CD95 (56 ± 13 % contre 27 ± 2 %, p  Conclusion Nous avons observe que les patients atteints de granulomatose eosinophilique avec polyangeite presentaient une polarisation lymphocytaire T de type Th2 et une tendance pour une polarisation Th9 et Th17, une activation lymphocytaire B et une diminution importante des ILC2 dans le sang peripherique lors des poussees. Cette diminution pourrait suggerer un recrutement accru de ces cellules au niveau des sites inflammatoires. L’augmentation de l’IL-25, de TSLP de TARC et des cytokines TH2 dans le serum des patients actifs renforce l’hypothese d’un dialogue entre l’immunite innee et l’immunite adaptative au cours de cette pathologie ou les ILC2 joue vraisemblablement un role important.

Caractéristiques phénotypiques et fonctionnelles des sous-populations lymphocytaires au cours de la granulomatose éosinophilique avec polyangéite

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Pathophysiology of systemic sclerosis: state of the art in 2014.

Proteomic Analysis of Human Scleroderma Fibroblasts Response to Transforming Growth Factor-ß.

Caractéristiques phénotypiques et fonctionnelles des sous-populations lymphocytaires au cours de la granulomatose éosinophilique avec polyangéite