Angiotensin-converting enzyme 2, a SARS-CoV-2 receptor, is upregulated by interleukin-6 via STAT3 signaling in rheumatoid synovium
Authors: Mokuda et al.
Link to paper: https://doi.org/10.1101/2020.05.26.115261
Journal/ Pre-Print: BioRxiv preprint
1. Active rheumatoid arthritis samples express more ACE2 protein by immunohistochemistry and more gene expression by RT-qPCR compared to inactive samples.
2. IL-6 + IL-6Rα stimulation of rheumatoid arthritis fibroblast-like cells increases ACE2 expression, and might be inhibited by siRNA of STAT3
The paper does not directly address COVID-19, but shows IL-6 signalling through STAT3 can upregulate ACE2 in primary synovial fibroblast-like cells from rheumatoid arthritis patients. ACE2 protein is increased in active rheumatoid arthritis immunohistochemistry samples and gene expression is upregulated in active synovial tissues. IL-6 + IL-6Rα stimulation upregulates ACE2, supposedly in a STAT3-dependent manner. They propose the increased IL-6 in COVID-19 patients may increase ACE2 expression, but only demonstrate this in synovial cells from rheumatoid arthritis patients.
Impact for SARS-CoV2/COVID19 research efforts
Understand ACE2 expression in synovial tissues of rheumatoid arthritis patients
ACE2 is involved in the viral entry of SARS-CoV-2, this study observes ACE2 expression in RA (autoimmune disease) and by IL-6 (inflammatory cytokine).
· In vitro study
· Tissue sections from RA patients
Strengths and limitations of the paper
Novelty: IL-6 upregulates ACE2 expression in the synovium.
Standing in the field: Rheumatoid arthritis drugs are already being investigated for COVID-19 treatment (e.g. anti-IL-6 tocilizumab).
No direct link between synovial ACE2 expression and COVID-19.
No direct clinical relevance of synovium in disease severity.
Appropriate statistics: ANOVA with post-hoc comparisons should be used in (C) and (D) where Student’s T-test was incorrectly used.
Viral model used: No viral model.
Translatability: Far from translatable. A link between synovium and COVID-19, or RA and COVID-19 should be made, or relevant cell type observed.
Main limitations: No direct use of, or relation to SARS-CoV-2 apart from ACE2.
No direct link of synovium to COVID-19 demonstrated.
Did not show STAT pathway phosphorylation or ACE2 protein expression upon stimulation (only RT-qPCR and ACE2).
Should increase n > 3; correct statistics might render results insignificant.