Unraveling the NALP-3/IL-1β Inflammasome

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Unraveling the NALP-3/IL-1β Inflammasome Charles A. Dinarello  Immunity  Volume 20, Issue 3, Pages 243-244 (March 2004) DOI: 10.1016/S1074-7613(04)00055-X Copyright © 2004 Cell Press Terms and Conditions

Figure 1 Role of the IL-1β Inflammasome in the Activation of Caspase-1 and Release of Active IL-1β Human monocytes stimulated with endotoxin accumulate inactive IL-1β precursors in the cytosol. Inactive pro-caspase-1 is constitutively present in these cells. The IL-1β inflammasome, composed of a scaffold of interacting proteins, activates pro-caspase-1. The caspase-recruitment domain (CARD) on the pro-caspase-1 interacts with CARD of an adaptor protein called ASC. The pyrin (PYD) domain of ASC binds to the PYD domain of NALP-3. NALP-3 is comprised of the NACHT domain, in which each of the mutations of Muckle-Wells syndrome are found; the NALP-associated domain (NAD); and ends with leucine-rich repeats (LRR). The CARD of caspase-1 also interacts with CARD of a protein called Cardinal, which binds to NACHT in NALP-3 with its N-terminal domain (FIIND). The oligomerization of these proteins results in activation of caspase-1, which then associates with the IL-1β precursor at the inner leaflet of the cell's membrane. There cleavage takes place and active IL-1β is secreted from the cell. It is likely that more than one mechanism is involved in the secretion event. In monocytes from subjects with Muckle-Wells syndrome bearing the mutation in NACHT (R260W), greater amounts of active IL-1β are found in the extracellular compartment compared to cells without the mutation. High levels of secreted active IL-1β likely leads to local and systemic inflammation associated with the mutation since the IL-1 receptor antagonist reverses the syndrome within days. Immunity 2004 20, 243-244DOI: (10.1016/S1074-7613(04)00055-X) Copyright © 2004 Cell Press Terms and Conditions