biostudies-literatureBertheloot DDeutsche ForschungsgemeinschaftEuropean Research Councile15415https://www.ebi.ac.uk/biostudies/studies/S-EPMC9174887biostudies-literatureUnknown14(6)Inflammasomes sense intracellular clues of infection, damage, or metabolic imbalances. Activated inflammasome sensors polymerize the adaptor ASC into micron-sized "specks" to maximize caspase-1 activation and the maturation of IL-1 cytokines. Caspase-1 also drives pyroptosis, a lytic cell death characterized by leakage of intracellular content to the extracellular space. ASC specks are released among cytosolic content, and accumulate in tissues of patients with chronic inflammation. However, if extracellular ASC specks contribute to disease, or are merely inert remnants of cell death remains unknown. Here, we show that camelid-derived nanobodies against ASC (VHH_ASC ) target and disassemble post-pyroptotic inflammasomes, neutralizing their prionoid, and inflammatory functions. NoEMBO molecular medicineNanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo.PMC9174887714175TRR237‐369799452EXC 2151‐390873048PLAT‐IL‐1322568668Wuerth JDWanderley CWDuthie FSchneider AHBertheloot DTesfamariam YMSchiffelers LDRosero NMaasewerd STodtmann JMRohland CSchmidt FICunha FQHawwari IRibeiro LSJenster LMFranklin BSfalseNanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo.Inflammasomes sense intracellular clues of infection, damage, or metabolic imbalances. Activated inflammasome sensors polymerize the adaptor ASC into micron-sized "specks" to maximize caspase-1 activation and the maturation of IL-1 cytokines. Caspase-1 also drives pyroptosis, a lytic cell death characterized by leakage of intracellular content to the extracellular space. ASC specks are released among cytosolic content, and accumulate in tissues of patients with chronic inflammation. However, if extracellular ASC specks contribute to disease, or are merely inert remnants of cell death remains unknown. Here, we show that camelid-derived nanobodies against ASC (VHH_ASC ) target and disassemble post-pyroptotic inflammasomes, neutralizing their prionoid, and inflammatory functions. No2022-01-01T00:00:00Z2022 Jun2025-04-19T17:36:41.612Z2025-02-19T03:58:47.173ZS-EPMC91748873543823810.15252/emmm.202115415