Abstract
TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1β. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1β was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1β was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction.
Highlights
Macrophages can be activated by a variety of pathogenand damage-associated molecular patterns (PAMPs and DAMPs) and are of major importance for innate immunity and tissue repair[1,2]
In a previous study, we found that stimulation of the non-death receptor TNFR2 alone is fully sufficient to induce necroptosis in caspase-inhibited macrophages[14]
TNFR2 crucially contributes to necroptosis beyond triggering of tumor necrosis factor (TNF) production by depletion of TRAF2-cIAP1/2 complexes sensitizing macrophages for TNFR1-induced necroptosis
Summary
Macrophages can be activated by a variety of pathogenand damage-associated molecular patterns (PAMPs and DAMPs) and are of major importance for innate immunity and tissue repair[1,2]. Activated macrophages act as phagocytes of pathogens and dead cells and connect innate immunity with adaptive immunity by antigen presentation to T-helper cells and release of pleiotropic cytokines such as interferons and tumor necrosis factor (TNF). The latter is a major effector molecule of activated macrophages and. A soluble form of TNF originates from transmembrane TNF by proteolytic processing[16]. Both forms of TNF bind to two receptors of the TNF receptor superfamily (TNFRSF), TNFR1 and TNFR2. Binding of soluble TNF by TNFR1 is fully sufficient for receptor activation, soluble TNF poorly stimulates TNFR2 signaling despite high-affinity binding[16]
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