Macrophages guard endothelial lineage by hindering endothelial-to-mesenchymal transition: Implications for the pathogenesis of systemic sclerosis

Pier Andrea Nicolosi, Enrico Tombetti, Anna Giovenzana, Eleonora Done, Eleonora Pulcinelli, Raffaella Meneveri, Mario Tirone, Norma Maugeri, Patrizia Rovere-Querini, Angelo A. Manfredi, Silvia Brunelli

Research output: Contribution to journalArticlepeer-review

Abstract

The signals that control endothelial plasticity in inflamed tissues have only been partially characterized. For example, it has been shown that inadequate vasculogenesis in systemic sclerosis (SSc) has been associated with an endothelial defect. We used a genetic lineage tracing model to investigate whether endothelial cells die or change phenotypically after fibrosis induction and whether signals released by cells of the innate immune system and in the blood of patients influence their commitment. We observed that in the lineage-tracing transgenic mice Cdh5-CreERT2::R26R-EYFP, endothelial-derived cells (EdCs) underwent fibrosis after treatment with bleomycin, and EdCs retrieved from the lung showed expression of endothelial-to-mesenchymal transition (EndoMT) markers. Liposome-encapsulated clodronate was used to assess macrophage impact on EdCs. Clodronate treatment affected the number of alternatively activated macrophages in the lung, with upregulated expression of EndoMT markers in lung EdCs. Endothelial fate and function were investigated in vitro upon challenge with serum signals from SSc patients or released by activated macrophages. Sera of SSc patients with anti-Scl70 Abs, at higher risk of visceral organ fibrosis, induced EndoMT and jeopardized endothelial function. In conclusion, EdCs in SSc might be defective because of commitment to a mesenchymal fate, which is sustained by soluble signals in the patient's blood. Macrophages contribute to preserve the endothelial identity of precursor cells. Altered macrophage-dependent plasticity of EdCs could contribute to link vasculopathy with fibrosis.

Original languageEnglish
Pages (from-to)247-258
Number of pages12
JournalJournal of Immunology
Volume203
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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