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Immunology: Spreading inflammation

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The NLRP3 inflammasome is an intracellular complex that activates caspase-1, resulting in the maturation and secretion of interleukin-1 (IL-1) and IL-18. Two reports by Franklin et al. and Baroja-Mazo et al. find that components of the NLRP3 inflammasome can be released from cells and can activate caspase-1 both extracellularly and in macrophages that phagocytose the secreted inflammasome proteins (Nat. Immunol. 15, 727–737 and 738–748, 2014).

Caspase-1 has previously been found extracellularly in cell supernatants. The two groups independently found all of the components of the NLRP3 inflammasome in macrophage supernatants. They further showed that NLRP3 and the adaptor protein ASC could form oligomeric complexes outside of the cell that can activate caspase-1 both extracellularly and when complexes containing ASC are ingested by macrophages. The authors propose that the inflammasome is released from cells upon induction of pyroptosis, or inflammatory cell death. Bystander macrophages that take up extracellular inflammasome components can thus increase the amount of caspase-1 produced, thereby amplifying cell death and tissue damage. The findings suggest a way that inflammation might spread through tissues.

As for the disease implications of the findings, patients with cryopyrin-associated periodic syndrome (CAPS) have dysregulated IL-1 levels due to gain-of-function mutations in NRLP3. Baroja-Mazo et al. showed that during active disease, patients with CAPS had higher levels of ASC-containing complexes in their blood than healthy controls. Franklin et al. reported that some individuals with autoimmune disease have anti-ASC antibodies that may enhance phagocytosis of extracellular ASC complexes. These aggregates in the blood may play a role in propagating the pathology of CAPS, and possibly autoimmune diseases, by activating the intracellular NLRP3 inflammasome in macrophages that ingest the ASC complexes.

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Farrell, A. Immunology: Spreading inflammation. Nat Med 20, 813 (2014). https://doi.org/10.1038/nm.3662

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