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

Abstract

SummaryIn 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.

Highlights

Tumor necrosis factor (TNF) is a homotrimeric pro-inflammatory and immunomodulatory cytokine
The expression of transmembrane tumor necrosis factor (tmTNF) before and after stimulation with LPS + IFN-g was similar in bone-marrowderived macrophages (BMDMs) from wild type (WT) and 3TG mice, suggesting an equivalent capacity to interact with its ligands (Figure S1E)
We investigated the interaction of soluble TNF receptor 2 (ETA) with tmTNF in BMDMs from 3TG mice

Summary

Introduction

Tumor necrosis factor (TNF) is a homotrimeric pro-inflammatory and immunomodulatory cytokine. Like most members of the TNF superfamily, it exists either in a transmembrane form (transmembrane tumor necrosis factor [tmTNF]) or in a soluble form (soluble tumor necrosis factor [sTNF]) after cleavage of its precursor—(tmTNF)—by the protease TACE (TNF alpha converting enzyme, ADAM17). Both forms are bioactive (Moss et al, 1997; Zheng et al, 2004). TNFR1 is ubiquitously expressed on most cells and its stimulation leads to the activation of pro-inflammatory or apoptotic/necroptotic pathways depending on the context. In addition to its pro-inflammatory role, TNFR2 could act as an anti-inflammatory mediator and as such plays a role in cell signaling and promotes cell survival (Wajant et al, 2003)

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