1. An Inflammatory Perspective on Necroptosis
Conor J. Kearney, Seamus J. Martin 
Molecular Cell 
Volume 65, Issue 6, Pages (March 2017)
DOI: /j.molcel
Copyright © 2017 Elsevier Inc. Terms and Conditions

2. Figure 1
Divergent Modes of Cell Death Differ with Respect to DAMP Release
Apoptosis typically minimizes inflammation through sequestration and inactivation of intracellular DAMPs as a consequence of early recognition and removal of apoptotic cells via local phagocytes. Necrotic cell death promotes liberation of intracellular DAMPs (such as members of the extended IL-1 cytokine family) to promote inflammation. Certain stimuli (e.g., TNF, TLR3 engagement) that normally result in caspase-dependent apoptosis can be shifted to necroptosis (i.e., programmed necrosis) via inhibition of caspase activation, thereby also resulting in DAMP release.
Molecular Cell  , DOI: ( /j.molcel )
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3. Figure 2 PAMP-Elicited Cytokines and Chemokines Promote Inflammation
Conserved components of diverse pathogens (i.e., PAMPs) are sensed via pattern recognition receptors (PRRs) such as Toll-like receptors. Upon stimulation, PRRs promote rapid expression of multiple pro-inflammatory cytokines and chemokines that coordinate the inflammatory response, leading to pathogen clearance and wound healing. Similar to PAMPs, TNF also promotes the expression of a similar cohort of classical inflammatory cytokines and chemokines in diverse cell types.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2017 Elsevier Inc. Terms and Conditions

4. Figure 3 TNF Induces Necroptosis when Caspases are Inhibited
Under normal circumstances, TNF receptor stimulation promotes recruitment of TRADD, RIPK1, and TRAF2 to the cytoplasmic tails of trimerised TNF receptors. cIAPs then ubiquitinate RIPK1, leading to recruitment of the TAK/TAB complex, which drives NF-κB activation and inflammatory cytokine/chemokine production (not shown). However, if RIPK1 fails to be sufficiently ubiquitinated via IAPs, RIPK1 can promote activation of caspase-8, via FADD, in a complex that has been dubbed the “RIPoptosome,” and this can lead to apoptosis. Where caspase-8 activation is blocked (through synthetic or viral-derived caspase inhibitors), RIPK1 can associate with RIPK3 and MLKL in a “necrosome” complex. Upon activation within the necrosome, RIPK3 phosphorylates MLKL, and this promotes oligomerization and insertion of the latter into the plasma membrane to execute necroptosis.
Molecular Cell  , DOI: ( /j.molcel )
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5. Figure 4
TNF Signaling Typically Promotes the Expression of Inflammatory Cytokines and Chemokines, but Can Be Switched to Apoptosis or Necroptosis
Most cell types respond to TNF by activating NF-κB, which directs the synthesis and secretion of numerous pro-inflammatory cytokines and chemokines (middle). However, upon inhibition of TNF-driven NF-κB activity (e.g., in the presence of inhibitors of transcription or translation), TNF stimulation results in apoptosis (left), as well as diminished production of inflammatory cytokines. If caspase-8 activity is absent or blocked, TNF stimulation can induce necroptosis (in cells that express RIPK3), leading to rapid loss of cell viability and early termination of TNF-induced synthesis of classical cytokines/chemokines. In the latter case, DAMP release might compensate for the shutdown of classical cytokines/chemokine synthesis, but this is likely to be context dependent.
Molecular Cell  , DOI: ( /j.molcel )
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6. Figure 5 Inflammatory Outcomes of TNF Stimulation
The outcome of shifting TNF- or TLR-induced signaling to necroptosis depends on the net loss of classical cytokines/chemokine synthesis versus the increase in DAMP release.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2017 Elsevier Inc. Terms and Conditions