TNFR1 and TNFR2 in the Control of the Life and Death Balance of Macrophages.

Daniela Siegmund,Harald Wajant

doi:10.3389/fcell.2019.00091

Abstract

Macrophages stand in the first line of defense against a variety of pathogens but are also involved in the maintenance of tissue homeostasis. To fulfill their functions macrophages sense a broad range of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) by plasma membrane and intracellular pattern recognition receptors (PRRs). Intriguingly, the overwhelming majority of PPRs trigger the production of the pleiotropic cytokine tumor necrosis factor-alpha (TNF). TNF affects almost any type of cell including macrophages themselves. TNF promotes the inflammatory activity of macrophages but also controls macrophage survival and death. TNF exerts its activities by stimulation of two different types of receptors, TNF receptor-1 (TNFR1) and TNFR2, which are both expressed by macrophages. The two TNF receptor types trigger distinct and common signaling pathways that can work in an interconnected manner. Based on a brief general description of major TNF receptor-associated signaling pathways, we focus in this review on research of recent years that revealed insights into the molecular mechanisms how the TNFR1-TNFR2 signaling network controls the life and death balance of macrophages. In particular, we discuss how the TNFR1-TNFR2 signaling network is integrated into PRR signaling.

Highlights

Tumor necrosis factor-alpha (TNF) is a highly pleiotropic cytokine that affects practically any type of cell
Since TRAF2 interacts with high affinity with TNFR1-associated death domain (TRADD) outside its death domain (DD) (Park et al, 2000), these findings suggest that TNF receptor 1 (TNFR1)-bound TRADD, and to a lesser extent TNFR1-bound receptor interacting protein kinase1 (RIPK1), recruit TRAF2 homotrimers into the TNFR1 signaling complex
There are a considerable number of high quality publications addressing the role of TNF in the life death balance of macrophages

Summary

INTRODUCTION

Tumor necrosis factor-alpha (TNF) is a highly pleiotropic cytokine that affects practically any type of cell. In context of TNFR1 signaling, TRADD, RIPK1, TRAF2 and TAK1 are of central relevance for the activation of the classical NFκB pathway and suppression of the cell death inducing capacity of TNFR1 but are responsible for triggering the MAP kinase cascades leading to the activation of JNK and p38 (Wajant et al, 2003). Due to the relevance of TRAF2 and cIAPs for preventing apoptosis and necroptosis in context of TNFR1 signaling, TNFR2-mediated depletion/degradation of these molecules can result in enhanced TNFR1-induced cell death in macrophages as is discussed below in detail. An intensively studied example is killing of human alveolar and monocytederived macrophages by in vitro infection with mycobacteria

Evidence References

CONCLUSION AND PERSPECTIVE