title: 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 undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. In this article, we report a key role for TNF/TNFR1 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 subpopulation was necessary for maximal apoptosis in the population of highly injected cells, and TNFR-deficient mice displayed enhanced susceptibility to Yersinia infection. 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.
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104.|Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Lance W
authors.identifier: 0000-0003-2458-6678
authors.initials: LW
authors.lastname: Peterson
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104.|Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Naomi H
authors.initials: NH
authors.lastname: Philip
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Christopher P
authors.identifier: 0000-0002-9458-0266
authors.initials: CP
authors.lastname: Dillon
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422.
authors.forename: Peter J
authors.identifier: 0000-0002-5110-9300
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104; ibrodsky@vet.upenn.edu.|Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Igor E
authors.identifier: 0000-0001-7970-872X
authors.initials: IE
authors.lastname: Brodsky
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death; D007113:Immunity, Innate; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology*; D051379:Mice; D010957:Plasmids / Q000235:genetics; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D015009:Yersinia Infections / Q000276:immunology*; D015011:Yersinia pseudotuberculosis / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001426:Bacterial Proteins; D020170:Caspase 1; D007770:L-Lactate Dehydrogenase; D051197:Toll-Like Receptor 4; D048069:Tumor Necrosis Factors; C476286:Ticam1 protein, mouse; C109227:YopP protein, Yersinia