摘要：SummaryIn order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signalingin 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.Graphical abstractDisplay OmittedHighlights•In vivodemonstration of tmTNF reverses signaling existence•tmTNF reverse signaling induces anti-oxidative stress response•tmTNF reverse signaling induces an arginase-1-mediated anti-inflammatory response•Reverse signaling is a complementary mechanism to TNF neutralization by anti-TNFImmunology; Cell Biology
