Angiopoietin-2 promotes inflammatory activation in monocytes of systemic sclerosis patients

Tiago Carvalheiro, Ana P. Lopes, Maarten van der Kroef, Beatriz Malvar-Fernandez, Carlos Rafael-Vidal, Anneline C. Hinrichs, Nila H. Servaas, Femke Bonte-Mineur, Marc R. Kok, Lorenzo Beretta, Maili Zimmermann, Wioleta Marut, Jose M. Pego-Reigosa, Timothy R.D.J. Radstake, Samuel Garcia

Research output: Contribution to journalArticlepeer-review

Abstract

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-α) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc.

Original languageEnglish
Article number9544
Pages (from-to)1-10
Number of pages10
JournalInternational Journal of Molecular Sciences
Volume21
Issue number24
DOIs
Publication statusPublished - Dec 2 2020

Keywords

  • Angiopoietin-2
  • Interleukin-6
  • Interleukin-8
  • Monocyte activation
  • Systemic sclerosis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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