Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis–Specific Transcriptional Signatures in Human Skin

Thuong Trinh-Minh, Andrea Hermina Györfi, Michal Tomcik, Cuong Tran-Manh, Xiang Zhou, Nicholas Dickel, Bilgesu Safak Tümerdem, Alexander Kreuter, Sven Niklas Burmann, Signe Vedel Borchert, Rizwan Iqbal Hussain, Jonas Hallén, Jörg Klingelhöfer, Meik Kunz, Jörg H.W. Distler*

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

Objective.
S100A4 is a DAMP protein. S100A4 is overexpressed in patients with systemic sclerosis (SSc), andlevels correlate with organ involvement and disease activity. S100A4−/−mice are protected fromfibrosis. The aim ofthis study was to assess the antifibrotic effects of anti-S100A4 monoclonal antibody (mAb) in murine models of SScand in precision cut skin slices of patients with SSc.
Methods.
The effects of anti-S100A4 mAbs were evaluated in a bleomycin-induced skinfibrosis model and inTsk-1 mice with a therapeutic dosing regimen. In addition, the effects of anti-S100A4 mAbs on precision cut SSc skinslices were analyzed by RNA sequencing.
Results.
Inhibition of S100A4 was effective in the treatment of pre-established bleomycin-induced skinfibrosis andin regression of pre-establishedfibrosis with reduced dermal thickening, myofibroblast counts, and collagen accumu-lation. Transcriptional profiling demonstrated targeting of multiple profibrotic and proinflammatory processes relevantto the pathogenesis of SSc on targeted S100A4 inhibition in a bleomycin-induced skinfibrosis model. Moreover, tar-geted S100A4 inhibition also modulated inflammation- andfibrosis-relevant gene sets in precision cut SSc skin slicesin an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP-activated protein kinase,calsequestrin-1, and phosphorylated STAT3, were validated on the protein level, and STAT3 inhibition was shown toprevent the profibrotic effects of S100A4 onfibroblasts in human skin.
Conclusion.
Inhibition of S100A4 confers dual targeting of inflammatory andfibrotic pathways in complementarymouse models offibrosis and in SSc skin. These effects support the further development of anti-S100A4 mAbs asdisease-modifying targeted therapies for SSc.
OriginalsprogEngelsk
TidsskriftArthritis and Rheumatology
Vol/bind76
Udgave nummer5
Sider (fra-til)783-795
Antal sider13
ISSN2326-5191
DOI
StatusUdgivet - maj 2024

Bibliografisk note

Funding Information:
Supported by the German Research Foundation (grants DI 1537/14‐1, DI 1537/17‐1, DI 1537/20‐1, DI 1537/22‐1, DI 1537/23‐1), SFB CRC1181 (project C01) and SFB TR221/project 324392634 (B04) of the German Research Foundation, the Wilhelm‐Sander‐Foundation (grant 2013.056.1), the Else‐Kröner‐Fresenius‐Foundation (grants 2014_A47 and 2014_A184), the German Federal Ministry of Education and Research (BMBF), MASCARA program, TP 2 (01EC1903A), and a Career Support Award of Medicine of the Ernst Jung Foundation to Prof. Dr. med. Distler. Further support was provided by the BMBF, CompLS program (grant 031L0262C to Mr Dickel and Dr Kunz), the German Research Foundation (SFB TR221/project 324392634 INF to Dr Kunz), GRK 2740 (B02 to Dr Kunz), the Ministry of Health Czech Republic (grant 023728 to Prof. Tomcik), the ELAN‐Foundation Erlangen (grant 21‐07‐23‐1 to Dr Györfi), as well as the Research Committee of the Medical Faculty of the Heinrich‐Heine University Düsseldorf (ID 2022‐18 to Dr Györfi). The study was also supported by project‐specific funding of Arxx Therapeutics.

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