Immunoglobulin G of systemic sclerosis patients programs a pro-inflammatory and profibrotic phenotype in monocyte-like THP-1 cells

Sripriya Murthy, Melanie Wannick, Georgios Eleftheriadis, Antje Müller, Jiao Luo, Hauke Busch, Anja Dalmann, Gabriela Riemekasten, Christian D. Sadik*

*Corresponding author for this work
4 Citations (Scopus)

Abstract

Objectives: Functional IgG autoantibodies against diverse G protein-coupled receptors, i.e. antibodies with agonistic or antagonistic activity at these receptors, are abundant in human serum. Their levels are altered in patients with SSc, and autoantibodies against angiotensin II receptor 1 (ATR1) and endothelin receptor A (ETA) have been suggested to drive SSc by inducing the chemokines CXCL8 and CCL18 in the blood. The objective of our study is to profile the effect of IgG in SSc (SSc-IgG) on the production of soluble mediators in monocytic cells. Methods: Monocyte-like THP-1 cells were stimulated with SSc-IgG and their secretome was analysed. Furthermore, the significance of major pro-inflammatory pathways for the induction of CXCL8 and CCL18 in response to SSc-IgG was assessed by a pharmacological approach. Results: Stimulation with SSc-IgG significantly alters the secretome of THP-1 cells towards a general pro-inflammatory and profibrotic phenotype, which includes an increase of CCL18 and CXCL8. The consequent expression profiles vary depending on the individual donor of the SSc-IgG. CCL18 and CXCL8 expression is thus regulated differentially, with AP-1 driving the induction of both CCL18 and CXCL8 and the TAK/IKK-β/NF-κB pathway and ERK1/2 driving that of CXCL8. Conclusions: Our results suggest that SSc-IgG contributes to the generation of the pro-inflammatory/profibrotic tissue milieu characteristic of SSc by its induction of a respective phenotype in monocytes. Furthermore, our results highlight AP-1 as a critical regulator of gene transcription of CCL18 in monocytic cells and as a promising pharmacological therapeutic target for the treatment of SSc.

Original languageEnglish
JournalRheumatology (United Kingdom)
Volume60
Issue number6
Pages (from-to)3012-3022
Number of pages11
ISSN1462-0324
DOIs
Publication statusPublished - 01.06.2021

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 204-05 Immunology

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