Research Article: Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death

Date Published: October 13, 2016

Publisher: Public Library of Science

Author(s): Naomi H. Philip, Alexandra DeLaney, Lance W. Peterson, Melanie Santos-Marrero, Jennifer T. Grier, Yan Sun, Meghan A. Wynosky-Dolfi, Erin E. Zwack, Baofeng Hu, Tayla M. Olsen, Anthony Rongvaux, Scott D. Pope, Carolina B. López, Andrew Oberst, Daniel P. Beiting, Jorge Henao-Mejia, Igor E. Brodsky, David Weiss.

http://doi.org/10.1371/journal.ppat.1005910

Abstract

Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.

Partial Text

Pattern recognition receptors such as Toll-like receptors (TLRs) sense conserved microbial structures including lipopolysaccharide (LPS) or peptidoglycans [1]. Bacterial infection triggers MyD88- and TRIF-dependent MAPK and NF-κB signaling, which induces the expression of cell survival and inflammatory programs that are critical for host defense [2]. Activation of TLRs in the presence of pharmacological or bacterial inhibitors of NF-κB results in cell death that is mediated by the cysteine protease caspase-8 [3–5]. This is due to recruitment of caspase-8 to a TRIF/RIPK1/FADD-containing complex via specific homotypic protein-protein interaction motifs [6]. RIPK1 interacts with TRIF by means of RIP homology interaction motifs (RHIM) and can bind FADD through shared death domains (DD), which in turn engages caspase-8 via death effector domains (DED) [7, 8]. Upon recruitment to this complex, caspase-8 undergoes dimerization and autoprocessing, which stabilizes the active enzyme, and initiates the proteolytic cascade that ultimately results in apoptotic disassembly of the cell [9].

Caspase-8 is a central regulator of cell fate decisions in the context of bacterial infection and inflammatory stimuli. The precise nature of the interactions between caspase-8 and a number of signaling and adapter proteins, such as cFLIP, RIPK1, RIPK3 and FADD, in the context of specific extracellular cues, determines whether the cell undergoes apoptosis, RIPK3-dependent programmed necrosis, or initiates inflammatory gene expression. Infection by the bacterial pathogen Yersinia induces innate immune cells to undergo caspase-8-mediated apoptosis, and it has been suggested that apoptosis of bacteria-infected cells promotes immune defense against infection [33, 61, 62]. However, whether caspase-8 controls anti-bacterial immune defense by regulating cell death or control of inflammatory cytokine production, as well as how caspase-8 controls inflammatory cytokine production during bacterial infection, remain unclear.

 

Source:

http://doi.org/10.1371/journal.ppat.1005910

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments