Research

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20 pages, 9561 KiB

Open AccessArticle

Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development

by Maria-Cristina Arcangeletti, Maria D’Accolti, Clara Maccari, Irene Soffritti, Flora De Conto, Carlo Chezzi, Adriana Calderaro, Clodoveo Ferri and Elisabetta Caselli

Int. J. Mol. Sci. 2020, 21(17), 6397; https://doi.org/10.3390/ijms21176397 - 03 Sep 2020

Cited by 15 | Viewed by 2386

Abstract

Systemic sclerosis (SSc) is a severe autoimmune disorder characterized by vasculopathy and multi-organ fibrosis; its etiology and pathogenesis are still largely unknown. Herpesvirus infections, particularly by human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6), have been suggested among triggers of the disease based [...] Read more.

Systemic sclerosis (SSc) is a severe autoimmune disorder characterized by vasculopathy and multi-organ fibrosis; its etiology and pathogenesis are still largely unknown. Herpesvirus infections, particularly by human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6), have been suggested among triggers of the disease based on virological and immunological observations. However, the direct impact of HCMV and/or HHV-6 infection on cell fibrosis and apoptosis at the cell microenvironment level has not yet been clarified. Thus, this study aimed to investigate the effects of HCMV and HHV-6 infection on the induction of pro-fibrosis or pro-apoptosis conditions in primary human dermal fibroblasts, one of the relevant SSc target cells. The analysis, performed by microarray in in vitro HCMV- or HHV-6-infected vs. uninfected cells, using specific panels for the detection of the main cellular factors associated with fibrosis or apoptosis, showed that both viruses significantly modified the expression of at least 30 pro-fibrotic and 20 pro-apoptotic factors. Notably, several recognized pro-fibrotic factors were highly induced, and most of them were reported to be involved in vivo in the multifactorial and multistep pathogenic process of SSc, thus suggesting a potential role of both HCMV and HHV-6. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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16 pages, 2020 KiB

Open AccessArticle

Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

by Roberto Lande, Anna Mennella, Raffaella Palazzo, Immacolata Pietraforte, Katia Stefanantoni, Nicoletta Iannace, Alessia Butera, Monica Boirivant, Roberta Pica, Curdin Conrad, Carlo Chizzolini, Valeria Riccieri and Loredana Frasca

Int. J. Mol. Sci. 2020, 21(14), 5102; https://doi.org/10.3390/ijms21145102 - 19 Jul 2020

Cited by 26 | Viewed by 2802

Abstract

Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to [...] Read more.

Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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9 pages, 1006 KiB

Open AccessCommunication

Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts

by Luigi Di Luigi, Paolo Sgrò, Guglielmo Duranti, Stefania Sabatini, Daniela Caporossi, Francesco Del Galdo, Ivan Dimauro and Cristina Antinozzi

Int. J. Mol. Sci. 2020, 21(9), 3161; https://doi.org/10.3390/ijms21093161 - 30 Apr 2020

Cited by 23 | Viewed by 2310

Abstract

Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud’s Phenomenon (RP) is a major risk factor for the development of SSc together with the presence [...] Read more.

Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud’s Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 µM H₂O₂), in the presence or absence of sildenafil (1 µM). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-κB-, and PKB/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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16 pages, 2121 KiB

Open AccessArticle

Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence

by Mirko Manetti, Eloisa Romano, Irene Rosa, Bianca Saveria Fioretto, Serena Guiducci, Silvia Bellando-Randone, Erika Pigatto, Franco Cozzi, Lidia Ibba-Manneschi and Marco Matucci-Cerinic

Int. J. Mol. Sci. 2019, 20(24), 6189; https://doi.org/10.3390/ijms20246189 - 07 Dec 2019

Cited by 9 | Viewed by 2668

Abstract

In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc [...] Read more.

In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc microenvironment may interfere with lymphangiogenesis, a complex, multi-step process in which lymphatic microvascular endothelial cells (LMVECs) sprout, migrate, and proliferate to generate new lymphatic capillaries. Normal human adult dermal LMVECs from three donors were treated with serum from SSc patients (n = 8), serum from healthy individuals (n = 8), or recombinant human vascular endothelial growth factor (VEGF)-C as a positive control for lymphangiogenesis. Cell proliferation, Boyden chamber Matrigel chemoinvasion, wound healing capacity, and lymphatic capillary morphogenesis on Geltrex were assayed. VEGF-C serum levels were measured by enzyme-linked immunosorbent assay. Gene and protein expression levels of the lymphangiogenic orchestrators VEGF receptor-3 (VEGFR-3)/Flt-4 and neuropilin-2 (NRP-2) were determined by real-time PCR and Western blotting, respectively. Conditioning with SSc serum significantly inhibited LMVEC proliferation, Matrigel invasion, and wound healing capacity with respect to healthy serum. The ability of LMVECs to form lymphatic tubes on Geltrex was also severely compromised in the presence of SSc serum. VEGF-C levels were comparable in SSc and healthy sera. Treatment with SSc serum resulted in a significant downregulation of both VEGFR-3/Flt-4 and NRP-2 mRNA and protein levels. In SSc, the pathologic environment severely hampers every lymphangiogenesis step, likely through the reduction of pro-lymphangiogenic VEGFR-3/NRP-2 co-receptor signaling. The impairment of the lymphangiogenic process opens a new scenario underlying SSc vascular pathophysiology, which is worth investigating further. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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Review

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24 pages, 884 KiB

Open AccessReview

Role of Alarmins in the Pathogenesis of Systemic Sclerosis

by Antonello Giovannetti, Elisabetta Straface, Edoardo Rosato, Marco Casciaro, Giovanni Pioggia and Sebastiano Gangemi

Int. J. Mol. Sci. 2020, 21(14), 4985; https://doi.org/10.3390/ijms21144985 - 15 Jul 2020

Cited by 9 | Viewed by 3283

Abstract

Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, [...] Read more.

Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing. In spite of intense investigation, both etiology and pathogenesis of SSc are still unknown. Genetic and environmental factors, as well as abnormalities of immune functions, are strongly suggested for etiology, while microvascular abnormalities, immune system activation, and oxidative stress are suggested for the pathogenesis. Recently, it has been found that a multitude of mediators and cytokines are implicated in the fibrotic processes observed in SSc. Among these, a central role could be exerted by “alarmins”, endogenous and constitutively expressed proteins/peptides that function as an intercellular signal defense. This review describes, in a detailed manner, the role of alarmins in the pathogenesis of scleroderma. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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20 pages, 398 KiB

Open AccessReview

Emerging Roles of Matricellular Proteins in Systemic Sclerosis

by Daniel Feng and Casimiro Gerarduzzi

Int. J. Mol. Sci. 2020, 21(13), 4776; https://doi.org/10.3390/ijms21134776 - 06 Jul 2020

Cited by 12 | Viewed by 2399

Abstract

Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, [...] Read more.

Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, which is a hallmark of fibrotic disease. A group of nonstructural matrix proteins, known as matricellular proteins (MCPs) are implicated in dysregulated processes that drive fibrosis such as ECM remodeling and various cellular behaviors. Accordingly, MCPs have been described in the context of fibrosis in sclerosis (SSc) as predictive disease biomarkers and regulators of ECM synthesis, with promising therapeutic potential. In this present review, an informative summary of major MCPs is presented highlighting their clear correlations to SSc- fibrosis. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

16 pages, 1196 KiB

Open AccessReview

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment

by Umberto Attanasio, Alessandra Cuomo, Flora Pirozzi, Stefania Loffredo, Pasquale Abete, Mario Petretta, Gianni Marone, Domenico Bonaduce, Amato De Paulis, Francesca Wanda Rossi, Carlo Gabriele Tocchetti and Valentina Mercurio

Int. J. Mol. Sci. 2020, 21(12), 4430; https://doi.org/10.3390/ijms21124430 - 22 Jun 2020

Cited by 20 | Viewed by 5104

Abstract

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct [...] Read more.

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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22 pages, 782 KiB

Open AccessReview

Exosomes in Systemic Sclerosis: Messengers Between Immune, Vascular and Fibrotic Components?

by Marta Colletti, Angela Galardi, Maria De Santis, Giacomo Maria Guidelli, Angela Di Giannatale, Luigi Di Luigi and Cristina Antinozzi

Int. J. Mol. Sci. 2019, 20(18), 4337; https://doi.org/10.3390/ijms20184337 - 04 Sep 2019

Cited by 36 | Viewed by 4286

Abstract

Systemic sclerosis (SSc) is a rare autoimmune disease, characterized by vasculopathy and fibrosis of the skin and internal organs. This disease is still considered incurable and is associated with a high risk of mortality, which is related to fibrotic events. An early diagnosis [...] Read more.

Systemic sclerosis (SSc) is a rare autoimmune disease, characterized by vasculopathy and fibrosis of the skin and internal organs. This disease is still considered incurable and is associated with a high risk of mortality, which is related to fibrotic events. An early diagnosis is useful for preventing complications, and targeted therapies reduce disease progression and ameliorate patients’ quality of life. Nevertheless, there are no validated biomarkers for early diagnosis with predictive prognostic value. Exosomes are membrane vesicles, transporting proteins and nucleic acids that may be delivered to target cells, which influences cellular behavior. They play important roles in cell–cell communication, both in physiological and pathological conditions, and may be useful as circulating biomarkers. Recent evidences suggest a role for these microvesicles in the three main aspects related to the pathogenesis of SSc (immunity, vascular damage, and fibrosis). Moreover, exosomes are of particular interest in the field of nano-delivery and are used as biological carriers. In this review, we report the latest information concerning SSc pathogenesis, clinical aspects of SSc, and current approaches to the treatment of SSc. Furthermore, we indicate a possible role of exosomes in SSc pathogenesis and suggest their potential use as diagnostic and prognostic biomarkers, as well as therapeutic tools. Full article

(This article belongs to the Special Issue New Insights into the Pathogenesis, Autoimmunity, and Management of Systemic Sclerosis)

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