TY - JOUR
T1 - Angiopoietin-2 promotes inflammatory activation in monocytes of systemic sclerosis patients
AU - Carvalheiro, Tiago
AU - Lopes, Ana P.
AU - van der Kroef, Maarten
AU - Malvar-Fernandez, Beatriz
AU - Rafael-Vidal, Carlos
AU - Hinrichs, Anneline C.
AU - Servaas, Nila H.
AU - Bonte-Mineur, Femke
AU - Kok, Marc R.
AU - Beretta, Lorenzo
AU - Zimmermann, Maili
AU - Marut, Wioleta
AU - Pego-Reigosa, Jose M.
AU - Radstake, Timothy R.D.J.
AU - Garcia, Samuel
N1 - Funding Information:
Funding: T.C. and A.P.L. were supported by grants from the Portuguese National Funding Agency for Science, Research and Technology: Fundação para a Ciência e a Tecnologia (SFRH/BD/93526/2013 and SFRH/BD/116082/2016 respectively). C. R-V. is supported by a predoctoral fellowship from Xunta de Galicia (IN606A-2020/043). S.G. is supported by the Miguel Servet program (CP19/00005) from the Instituto de Salud Carlos III (ISCIII) and the European Social Fund (“Investing in your future”).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/2
Y1 - 2020/12/2
N2 - 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.
AB - 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.
KW - Angiopoietin-2
KW - Interleukin-6
KW - Interleukin-8
KW - Monocyte activation
KW - Systemic sclerosis
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U2 - 10.3390/ijms21249544
DO - 10.3390/ijms21249544
M3 - Article
C2 - 33333969
AN - SCOPUS:85098144356
VL - 21
SP - 1
EP - 10
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 24
M1 - 9544
ER -