Title | RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Peterson LW, Philip NH, DeLaney A, Wynosky-Dolfi MA, Asklof K, Gray F, Choa R, Bjanes E, Buza EL, Hu B, Dillon CP, Green DR, Berger SB, Gough PJ, Bertin J, Brodsky IE |
Journal | J Exp Med |
Volume | 214 |
Issue | 11 |
Pagination | 3171-3182 |
Date Published | 2017 Nov 06 |
ISSN | 1540-9538 |
Keywords | Animals, Apoptosis, Cytokines, Disease Resistance, Host-Pathogen Interactions, Immunity, Innate, Macrophages, MAP Kinase Signaling System, Mice, Inbred C57BL, Mice, Knockout, Models, Immunological, NF-kappa B, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Survival Analysis, Yersinia pseudotuberculosis, Yersinia pseudotuberculosis Infections |
Abstract | Many pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed "effector-triggered immunity." The Gram-negative bacterial pathogen inactivates critical proteins of the NF-κB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. -induced apoptosis requires the kinase activity of receptor-interacting protein kinase 1 (RIPK1), a key regulator of cell death, NF-κB, and MAPK signaling. Through the targeted disruption of RIPK1 kinase activity, which selectively disrupts RIPK1-dependent cell death, we now reveal that -induced apoptosis is critical for host survival, containment of bacteria in granulomas, and control of bacterial burdens in vivo. We demonstrate that this apoptotic response provides a cell-extrinsic signal that promotes optimal innate immune cytokine production and antibacterial defense, demonstrating a novel role for RIPK1 kinase-induced apoptosis in mediating effector-triggered immunity to circumvent pathogen inhibition of immune signaling. |
DOI | 10.1084/jem.20170347 |
Alternate Journal | J. Exp. Med. |
PubMed ID | 28855241 |
PubMed Central ID | PMC5679171 |
Grant List | P30 DK050306 / DK / NIDDK NIH HHS / United States R01 AI128530 / AI / NIAID NIH HHS / United States R37 AI044828 / AI / NIAID NIH HHS / United States T32 GM007170 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm