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

Katy Diallo; Numa Simons; Souraya Sayegh; Michel Baron; Yannick Degboé; Jean-Frédéric Boyer; Andrey Kruglov; Sergei Nedospasov; Julien Novarino; Meryem Aloulou; Nicolas Fazilleau; Arnaud Constantin; Alain Cantagrel; Jean-Luc Davignon; Benjamin Rauwel

doi:10.1016/j.isci.2021.102331

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

iScience. 2021 Mar 21;24(4):102331. doi: 10.1016/j.isci.2021.102331. eCollection 2021 Apr 23.

Authors

Katy Diallo¹, Numa Simons^{1

2}, Souraya Sayegh¹, Michel Baron¹, Yannick Degboé^{1

2

3}, Jean-Frédéric Boyer², Andrey Kruglov^{4

5}, Sergei Nedospasov⁵, Julien Novarino¹, Meryem Aloulou¹, Nicolas Fazilleau¹, Arnaud Constantin^{1

2

3}, Alain Cantagrel^{1

2

3}, Jean-Luc Davignon^{1

2}, Benjamin Rauwel¹

Affiliations

¹ INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France.
² Centre de Rhumatologie, CHU de Toulouse, Toulouse, France.
³ Faculté de Médecine, Université Paul Sabatier Toulouse III, Toulouse, France.
⁴ German Rheumatism Research Center (DRFZ), a Leibniz Institute Berlin 10117, Germany.
⁵ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.

Abstract

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.

Keywords: Cell Biology; Immunology.