Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis

Abstract

Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells still undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. Here we report a previously undescribed role for TNF receptor signaling in Yersinia-induced cell death of murine macrophages, which occurs despite the blockade of NF-κB and MAPK signaling imposed by Yersinia on infected cells. Intriguingly, direct analysis of YopJ injection revealed a heterogeneous population of injection-high and injection-low cells, and demonstrated that TNF expression came from the injection-low population. Moreover, TNF production by this sub-population was necessary for maximal apoptosis in the population of highly injected cells. These data demonstrate an important role for collaboration between TNF and Pattern Recognition Receptor signals in promoting maximal apoptosis during bacterial infection, and demonstrate that heterogeneity in virulence factor injection and cellular responses play an important role in promoting anti-Yersinia immune defense.

The outer membrane protein Tp92 of Treponema pallidum induces human mononuclear cell death and IL‐8 secretion

“…Activation of TNFR, Fas and TNF‐related apoptosis‐inducing ligand receptors (TRAIL‐Rs or DR4/5) stimulates various downstream cell death pathways . However, only TNFR1 and Fas can induce downstream cell death pathways via RIPK1 . In recent years, researchers have found that TLRs can also activate downstream cell death pathways.…”

The in vivo evidence for regulated necrosis

“…In contrast, another subtype of fibrinoid necrosis is represented by precipitated fibrinoid which is associated with immune complex diseases. 40 Pyroptosis might also play a role in caseating necrosis, as intracellular pathogens are classical inducers of the NLRP3 inflammasome 41 and also activate caspase-11, 42 both of which are required to control bacteria that escape the vacuole. Mechanistic insights into the pathophysiological relevance of these immune complex-triggered necrotic areas came from mice that are deficient in LC3-associated phagocytosis (LAP, a form of noncanonical autophagy 36 ).…”

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

“…The acetyltransferase YopJ (YopP in Y. enterocolitica ) is a homologue of Salmonella AvrA that inhibits transforming growth factor beta‐activated kinase 1 (TAK1), IκB kinase β (IKKβ) and mitogen‐activated protein kinase (MAPK) kinases, inhibiting pro‐inflammatory signalling in response to TLR and/or TNF signalling (Peterson et al, ; Pinaud et al, ). TAK1 inhibition promotes non‐canonical RIPK1‐FADD‐caspase‐8‐dependent GSDMD cleavage, pore formation and cell death in mouse macrophages.…”

“…The resulting potassium efflux triggers NLRP3 and caspase‐1 activation, and release of IL‐1β (Philip et al, ; Orning et al, ) (Figure f). In addition, blockade of TNF‐mediated pro‐survival NF‐κB and MAPK signalling by YopJ can also lead to RIPK1‐dependent apoptosis (Weng et al, ; Peterson et al, ; Peterson et al, ). Further, YopJ‐mediated inhibition of the Nod2 pathway has also been linked to Nod2‐dependent activation of caspase‐1 and IL‐1β release from Peyer's patches, and loss of intestinal barrier function in mice (Meinzer et al, ).…”

“…The PYRIN inflammasome is activated through the RhoA GTPase-inhibiting activity of YopE and YopT (Chung et al, 2016;Ratner et al, 2016) ( Figure 2f). To counteract detection by the inflammasomes, Yersinia encodes the effector YopK, which interacts with the T3SS and regulates translocation of effectors (Brodsky et al, 2010;Zwack et al, 2015), and YopM, a homologue of the The acetyltransferase YopJ (YopP in Y. enterocolitica) is a homologue of Salmonella AvrA that inhibits transforming growth factor beta-activated kinase 1 (TAK1), IκB kinase β (IKKβ) and mitogenactivated protein kinase (MAPK) kinases, inhibiting pro-inflammatory signalling in response to TLR and/or TNF signalling (Peterson et al, 2016;Pinaud et al, 2018). TAK1 inhibition promotes non-canonical RIPK1-FADD-caspase-8-dependent GSDMD cleavage, pore formation and cell death in mouse macrophages.…”