Caspase-8 promotes c-Rel–dependent inflammatory cytokine expression and resistance against Toxoplasma gondii

Alexandra A. DeLaney, Corbett T. Berry, David A. Christian, Andrew Hart, Elisabet Bjanes, Meghan A. Wynosky-Dolfi, Xinyuan Li, Bart Tummers, Irina A. Udalova, Youhai H. Chen, Uri Hershberg, Bruce D. Freedman, Christopher A. Hunter, Igor E. Brodsky

Research output: Contribution to journalArticlepeer-review

Abstract

Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Following engagement of tumor necrosis factor superfamily receptors or certain Toll-like receptors (TLRs), caspase-8 initiates cell-extrinsic apoptosis while inhibiting RIPK3-dependent programmed necrosis. In addition, caspase-8 has an important, albeit less well understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 or the adaptor FADD have defective inflammatory cytokine expression and inflammasome priming in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8–mediated gene regulation has a physiological role during infection, remain poorly defined. Here we demonstrate that both caspase-8 enzymatic activity and scaffolding functions contribute to inflammatory cytokine gene expression. Caspase-8 enzymatic activity was necessary for maximal expression of Il1b and Il12b, but caspase-8 deficient cells exhibited a further decrease in expression of these genes. Furthermore, the ability of TLR stimuli to induce optimal IκB kinase phosphorylation and nuclear translocation of the nuclear factor kappa light chain enhancer of activated B cells family member c-Rel required caspase activity. Interestingly, overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1β in caspase-8–deficient cells. Moreover, Ripk3/Casp8/− mice were unable to control infection by the intracellular parasite Toxoplasma gondii, which corresponded to defects in monocyte recruitment to the peritoneal cavity, and exogenous IL-12 restored monocyte recruitment and protection of caspase-8–deficient mice during acute toxoplasmosis. These findings provide insight into how caspase-8 controls inflammatory gene expression and identify a critical role for caspase-8 in host defense against eukaryotic pathogens.

Original languageEnglish
Pages (from-to)11926-11935
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number24
DOIs
StatePublished - 11 Jun 2019
Externally publishedYes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Daniel Grubaugh and Daniel Sorobetea for technical assistance, scientific discussion, and editorial comments; Baofeng Hu for technical assistance; Walter Mowel, Dr. Jorge Henao Mejia, and members of the Shin laboratory for helpful scientific discussions; Dr. Maxime Jacquet, Dr. Anthony Phan, Dr. Jeong Ho Park, and Joe Clark for their assistance with parasite quantifications and parasite growth conditions; Drs. Hsiou-Chi Liou (Cornell University), Wendy Weinberg (US Food and Drug Administration), and Johannes Zakrzewski (Cornell University) for providing Rel−/− mice. This work was supported by National Science Foundation Graduate Research Fellowship 2016199777 (to A.A.D.), National Institutes of Health Grants R01 AI128530 and R01 AI125924, and a Burroughs Welcome Foundation PATH Award (to I.E.B.).

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.

Keywords

  • Caspase-8
  • IL-12
  • TLR signaling
  • Toxoplasma
  • c-Rel

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Caspase-8 promotes c-Rel–dependent inflammatory cytokine expression and resistance against Toxoplasma gondii'. Together they form a unique fingerprint.

Cite this