Evidence for tmTNF reverse signaling in vivo: Implications for an arginase-1-mediated therapeutic effect of TNF inhibitors during inflammation

iScience

Andrey Kruglov¹  Souraya Sayegh¹  Nicolas Fazilleau²  Sergei Nedospasov³  Julien Novarino⁴  Arnaud Constantin⁵  Meryem Aloulou⁶  Benjamin Rauwel⁷  Michel Baron⁷  Jean-Frédéric Boyer⁷  Yannick Degboé⁷  Jean-Luc Davignon⁷  Alain Cantagrel⁷  Numa Simons⁷  Katy Diallo⁷ 

[1] Centre de Rhumatologie, CHU de Toulouse, Toulouse, France;Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;Faculté de Médecine, Université Paul Sabatier Toulouse III, Toulouse, France;Centre de Rhumatologie, CHU de Toulouse, Toulouse, France;Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;German Rheumatism Research Center (DRFZ), a Leibniz Institute Berlin 10117, Germany;INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France;

关键词: Immunology;    Cell Biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1−/−, TNFR2−/−, and tmTNFKI/KI) in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.

【 授权许可】

Unknown