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Review
. 2017 Mar;17(3):151-164.
doi: 10.1038/nri.2016.147. Epub 2017 Jan 31.

V体育ios版 - Programmed cell death as a defence against infection

Ine Jorgensen  1 , Manira Rayamajhi  2 , Edward A Miao  3
Affiliations
Review

Programmed cell death as a defence against infection

"VSports手机版" Ine Jorgensen et al. Nat Rev Immunol. 2017 Mar.

Abstract

Eukaryotic cells can die from physical trauma, which results in necrosis. Alternatively, they can die through programmed cell death upon the stimulation of specific signalling pathways. In this Review, we discuss the role of different cell death pathways in innate immune defence against bacterial and viral infection: apoptosis, necroptosis, pyroptosis and NETosis. We describe the interactions that interweave different programmed cell death pathways, which create complex signalling networks that cross-guard each other in the evolutionary 'arms race' with pathogens. Finally, we describe how the resulting cell corpses - apoptotic bodies, pore-induced intracellular traps (PITs) and neutrophil extracellular traps (NETs) - promote the clearance of infection VSports手机版. .

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Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

V体育平台登录 - Figures

Figure 1
Figure 1. Pyroptosis
Pyroptosis is initiated by either caspases 1 or 11. Caspase 1 is activated by one of several inflammasomes, NOD-, LRR- and pyrin domain-containing 3 (NLRP3), AIM2, interferon-γ (IFNγ)-inducible protein 16 (IFI16), pyrin, NOD-, LRR- and CARD-containing 4 (NLRC4) and NLRP1b. NLRP3 responds to numerous agonists, which may converge upon low cellular potassium concentration, although this remains controversial. NLRP3 will not respond to these agonists unless it also receives a priming stimulus via various Toll-like receptors (TLRs) or from tumour necrosis factor (TNF), which trigger post-translational priming (probably de-ubiquitination), as well as boosting NLRP3 sensitivity by transcriptional induction. AIM2 detects cytosolic DNA,, and IFI16, which lacks a clear mouse homolog, also detects viral nucleic acids. Pyrin detects modulation of Rho-family GTPases by bacterial toxins. NLRC4 is activated by one of three bacterial flagellin or type III secretion rod or needle proteins that signal via an upstream NLR in the NAIP family,,,. NLRP1b detects the protease activity of the anthrax lethal toxin,. By contrast, caspase 11 itself is the sensor for cytosolic lipopolysaccharide (LPS)–. Similar to NLRP3, caspase 11 requires priming, but priming is by either type I interferon or interferon-γ (IFNγ). Either caspases 1 or 11 independently cleaves gasdermin D, from which the released N-terminal fragment associates with the cell membrane and oligomerizes to form the pyroptotic pore–. The cell then swells, resulting in membrane rupture that is called pyroptosis. In addition, caspase 1 will cleave pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to their mature forms (caspase 11 cannot do this directly). Mature IL-1β and IL-18 can escape through the gasdermin D pore, or be released later by membrane rupture,. Red and blue lines represent initiating and priming events, respectively.
Figure 2
Figure 2. Apoptosis and Necroptosis
(Left) Apoptosis can be triggered via intrinsic or extrinsic pathways, including by natural killer (NK) cells and cytotoxic T lymphocyte (CTL) granzymes. These stimulate the cleavage of BID to tBID, which causes BAX and/or BAK to trigger mitochondrial outer-membrane permeabilization (MOMP), resulting in release of cytochrome C (CytC), which binds to apoptotic protease activating factor 1 (APAF1). APAF1 then oligomerizes into the apoptosome, the platform for caspase 9 activation. Either caspases 8 or 9 will cleave the effector caspases 3 and 7 into their active forms, which leads to apoptosis. (Right) Necroptosis can be triggered by DNA-sensing via ZBP1, which activates receptor-interacting protein kinase 3 (RIPK3) followed by phosphorylation of MLKL. Phosphorylated MLKL binds to the inner leaflet of the plasma membrane and forms the necroptotic pore–. (Center) In the more complex necroptotic pathway, tumour necrosis factor receptor 1 (TNFR1), Toll-like receptor 3 (TLR3)–TRIF, or TLR4–TRIF signal via RIPK1 to activate NF-κb (but RIPK1 is not required for the TRIF-type I IFN response,). RIPK1 can be thought of as a finely balanced teeter-totter with two guards: caspase 8 on one side balanced by a duo of RIPK3 and ZBP1 on the other. When TNFR1–TLR3–TLR4 signalling proceed normally, RIPK1 is “balanced” and functions as a scaffolding protein that becomes poly-ubiquitinated, and serving as a platform for signalling complex assembly driving transcriptional responses. When signalling is inhibited, for example by inhibition of cIAP1/2 pharmacologic inhibitors (with SMAC mimetics), by inhibiting TAK1, by inhibition of protein synthesis, or by blocking RIPK1 ubiquitination , or potentially by virulence factors, RIPK1 becomes “unbalanced”. RIPK1 then recruits FADD (a DD-DED adaptor) via DD-DD interactions, and FADD recruits caspase 8 via DED-DED interaction thereby triggering extrinsic apoptosis–. Successful caspase 8 activation provides negative feedback to prevent necroptosis by cleaving RIPK1 and RIPK3 in the kinase domains,. However, inhibition of caspase-8 pharmacologically or by viral virulence factors permits continued RIPK1 kinase activity, and the teeter-totter swings the other direction. RIPK1 recruits RIPK3 via RHIM-RHIM interaction, and phosphorylates it, triggering RIPK3 kinase activity and necroptosis–. Thus, RIPK1, RIPK3, and caspase 8 act as a cross guard system for TNFR1, TLR3, and TLR4. TLRs such as TLR2 that do not signal through TRIF,,,, unless longer time points are examined where TLR2-driven TNF could require caspase 8 to cause paracrine TNFR1 stimulation.
Figure 3
Figure 3. Apoptotic bodies, neutrophil extracellular traps and pore-induced intracellular traps
The fate of the cell corpse is dependent on the cell death pathway. Extrinsic or intrinsic apoptosis leads to the formation of apoptotic bodies that are engulfed by a secondary phagocyte, a process that is referred to as efferocytosis. In the absence of efferocytosis, apoptotic bodies can undergo secondary necrosis. Lytic death of cells infected with an intracellular pathogen, including pyroptosis, leads the formation of a pore-induced intracellular trap (PIT), which traps the pathogen within the cell corpse. The PIT also presents ligands that are recognized by neutrophils (and potentially macrophages), which efferocytose the PITs and associated bacteria, ultimately killing the pathogen. Efferocytosis of pathogen-containing apoptotic bodies also eliminates the pathogen. Necroptosis and necrosis also result in PITs in vitro, although the physiologic importance in vivo needs further study. Following detection of extracellular pathogens, neutrophils extrude a meshwork of chromatin dotted with granules loaded with antimicrobial molecules. These neutrophil extracellular traps (NETs) trap and kill extracellular pathogens.
Figure 4
Figure 4. Interactions between apoptotic, necroptotic and pyroptotic pathways
Cell death pathways can interact with each other, with the caveat that once a cell death pathway runs to completion, the interaction ends. The exception to this is the lysis of apoptotic bodies by secondary necrosis, which releases cytosolic contents, effectively converting apoptosis to lytic cell death. Signalling pathways running through RIPK1 will fail if Casp8 is deleted, affecting priming of NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and caspase 11,,,–. Caspase 1 driven IL-18 can have two interactions with other pathways, first by inducing interferon-γ (IFNγ) production to prime caspase 11, and second by stimulating NK cytotoxic activity. The terminal events occurring after the MLKL or gasdermin D pores open are catastrophic, resulting in loss of cellular potassium, which is the trigger for NLRP3 activation,. In the window between potassium loss and membrane rupture, NLRP3 activity will trigger caspase 1-dependent processing of interleukin-1β (IL-1β) and IL-18 processing. Finally, ASC and caspase 1 can activate caspase 8, triggering apoptosis,,,. Purple lines are interacting pathways.
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