Macrophages in Systemic Sclerosis: Novel Insights and Therapeutic Implications

Toledo, Diana M; Pioli, Patricia A.

doi:10.1007/s11926-019-0831-z

Cited by 43 publications

(35 citation statements)

References 65 publications

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“…Of note, the vast majority of early diffuse SSc patients with a fibroblast signature had a concomitant M1 and/or M2 macrophage signature, and many had concomitant adaptive immune cell signatures, suggesting co-occurrence of dysregulated fibroblast and immune cell function in a majority of early diffuse SSc patients. Our gene expression and IHC data add to the large body of evidence that macrophages are upregulated in SSc 29 30. Macrophages are capable of detecting innate immune stimuli and producing both pro-inflammatory and pro-fibrotic cytokines, including some (eg, IL-6 and TGFβ) that are implicated in SSc pathogenesis.…”

Section: Discussionmentioning

confidence: 66%

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

et al. 2019

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ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

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Section: Discussionmentioning

confidence: 66%

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

et al. 2019

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“…In fact, failure to resolve macrophage activation can lead to chronic inflammation and fibrosis. For a detailed discussion of the therapeutic interventions that could be implemented by targeting activated macrophages in SSc, we refer the reader to a recent review (Toledo and Pioli, 2019).…”

Section: Sclerodermamentioning

confidence: 99%

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

Gregorio

Robuffo

Spalletta³

et al. 2020

Front. Cell Dev. Biol.

102

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Fibrosis is a chronic and progressive disorder characterized by excessive deposition of extracellular matrix, which leads to scarring and loss of function of the affected organ or tissue. Indeed, the fibrotic process affects a variety of organs and tissues, with specific molecular background. However, two common hallmarks are shared: the crucial role of the transforming growth factor-beta (TGF-β) and the involvement of the inflammation process, that is essential for initiating the fibrotic degeneration. TGF-β in particular but also other cytokines regulate the most common molecular mechanism at the basis of fibrosis, the Epithelial-to-Mesenchymal Transition (EMT). EMT has been extensively studied, but not yet fully explored as a possible therapeutic target for fibrosis. A deeper understanding of the crosstalk between fibrosis and EMT may represent an opportunity for the development of a broadly effective anti-fibrotic therapy. Here we report the evidences of the relationship between EMT and multi-organ fibrosis, and the possible therapeutic approaches that may be developed by exploiting this relationship.

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“…macrophages have been implicated in the pathogenesis of systemic sclerosis [54], [55] . Thererefore targeting therapeutic interventions directed against SSc in ammatory M1 macrophages may ameliorate in ammation and brosis [76].…”

Section: Discussionmentioning

confidence: 99%

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

Carella

Rossi

Ribuffo

et al. 2020

Preprint

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Background Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy and excessive production of collagen, which lead to skin and visceral fibrosis. The aim of our study is to assess the potential benefits of peripheral blood mononuclear cells (PB-MNCs) implants in the treatment of clinical manifestations such as mouth impairment, hand disability, digital ulcers and Raynaud’s phenomenon in Scleroderma patients. Methods From February 2016 to May 2019, 10 female patients were enrolled from the outpatient clinic of the Plastic Surgery Unit of Sapienza University of Rome. Parameters evaluated were: patients’ disability, using the Health Assessment Questionnaire (HAQ) disability index (DI) and the scleroderma HAQ (sHAQ); mouth opening capacity, by measuring the maximum interincisal distance and the mouth perimeter; hand mobility, assessed with clinical exam and the Hand Mobility in Scleroderma (HAMIS) scale; Raynaud’s phenomenon, evaluated through nailfold capillaroscopy; digital ulcers, examined through their features and incidence of appearance. SPSS software was used for a simple descriptive statistical analysis performed by the Student's paired t-test. P values less than 0.05 were considered statistically significant. Results The treatment showed a significant improvement of all the parameters evaluated at 1-year follow-up, it was well-tolerated by all the patients and the only complications noticed were small areas of ecchymosis. Conclusions Our results suggest that PB-MNCs injection could represent a treatment option to take into account for SSc patients. The procedure we used is easy and fast to perform, minimally invasive and not-operator dependent. We hope our observational and preliminary study could be considered as a starting point for further research studies.

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Macrophages in Systemic Sclerosis: Novel Insights and Therapeutic Implications

Cited by 43 publications

References 65 publications

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

The use of Peripheral Blood-Mononuclear Cells in Scleroderma patients: an observational preliminary study

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