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

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.

Keywords: TNF; TNFR1; TNFR2; apoptosis; caspase-8; necroptosis; ripk1; ripk3.

FIGURE 1

The TNF-TNFR1-TNFR2 system. As other receptors of the TNFRSF, TNFR1 and TNFR2 are characterized by cysteine-rich domains (CRD) in their extracellular part. TNFR1 harbors furthermore a death domain (DD) and TNFR2 a TRAF2 binding site (T2bs). TNF occurs in two forms, as a membrane-bound trimeric ligand (memTNF) and as a soluble likewise trimeric molecule (sTNF). TACE processes memTNF to sTNF. Please note, memTNF stimulates both TNF receptors while sTNF largely fails to stimulate TNFR2 despite high-affinity binding. PLAD, pre-ligand binding assembly domain.

FIGURE 2

TNFR1 signaling. The default state of TNFR1 signaling results in activation of proinflammatory pathways such as the classical NFκB pathway. If FLIP proteins and the TRAF2-cIAP1/2 complexes are limited, e.g., due to CHX treatment and/or TRAF2-cIAP1/2 depletion), the quality of TNFR1 signaling shifts to apoptosis. Not before caspase-8 activity is limited under apoptotic conditions, there is finally necroptosis induction. For more details see text.

FIGURE 3

TNFR2 signaling. TNFR2 efficiently recruits TRAF2-cIAP1/2 and TRAF1-TRAF2-cIAP1/2 complexes which allow activation of the classical NFκB pathway. TNFR2 recruitment of TRAF2-cIAP1/2 and TRAF1-TRAF2-cIAP1/2 complexes concomitantly depletes the cytosolic pool of these proteins and hinder them so to trigger degradation of the alternative NFκB pathway stimulating kinase NIK. Thus, TNFR2 also activates the alternative NFκB pathway.

FIGURE 4

The cytotoxic TLR-TNF signaling network. TNF expression is strongly upregulated by PRRs such as TLR3 and TLR4 via the classical NFκB pathway. TNF via the two TNF receptors can then cooperate with TLR3/4-TRIF-RIPK1 axis to trigger apoptosis or necroptosis. For details see text. Please note, necroptosis only takes place when caspase-8 activity is limited, e.g., by viral caspase-8 inhibitors.

FIGURE 5

The role of type I interferons in the cytotoxic TLR-TNF signaling network. TNF via the classical NFκB pathway induces IRF1 which in turn stimulates in cooperation with the classical NFκB pathway the expression of low amounts of IFNβ. The latter boosts its own expression by autocrine signaling but also the expression of pro-necroptotic proteins, such as TNFR2 and MLKL. PRRs, e.g., TLR4, often co-induce TNF and IFNβ expression. Thus, cytotoxic signaling by PRRs, IFNβ, and TNF are interconnected in various ways in macrophages by feed forward loops. Please be aware, for simplicity functional relevant phosphorylation and ubiquitination events are not included. For more details see text.