Cell death and autoinflammation

Lawlor KE1, Feltham R1, Yabal M2, Jost PJ2 and Vince JE1

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  2. III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar,Technische Universität München, 81675 Munich, Germany.

Cytosolic inflammasome sensor proteins activate caspase-1, resulting in cleavage-induced maturation and secretion of the potent inflammatory cytokine Interleukin-1β (IL-1β). Consequently, activating mutations in inflammasome sensor proteins result in autoinflammatory disease that can be treated with anti-IL-1 therapeutics. Surprisingly, recent studies have highlighted that mutations in components of the Toll-like Receptor (TLR) and TNF Receptor (TNFR) signaling machinery can also result in pathological IL-1β production, and autoinflammatory disease with symptoms reminiscent of patients with activating inflammasome mutations. How this aberrant TLR and TNF Receptor signaling can activate cytosolic inflammasome complexes remains unclear. In our recent studies we have explored this conundrum using a murine model of X-linked Inhibitor of Apoptosis (XIAP) deficiency, which can trigger potentially fatal, pathogen-associated, hyperinflammation in humans. We define a novel TLR and TNF Receptor cooperative signaling mechanism that is essential for inflammasome and IL-1β activation in the absence of XIAP, and document how this pathway may also act to generate pathological IL-1β responses in models of endotoxic shock and inflammatory arthritis.