TY  - JOUR
AU  - Bertheloot, Damien
AU  - Wanderley, Carlos WS
AU  - Schneider, Ayda H
AU  - Schiffelers, Lisa DJ
AU  - Wuerth, Jennifer D
AU  - Tödtmann, Jan MP
AU  - Maasewerd, Salie
AU  - Hawwari, Ibrahim
AU  - Duthie, Fraser
AU  - Rohland, Cornelia
AU  - Secchim Ribeiro, Lucas
AU  - Jenster, Lea-Marie
AU  - Rosero, Nathalia
AU  - Tesfamariam, Yonas M
AU  - Cunha, Fernando Q
AU  - Schmidt, Florian I
AU  - Franklin, Bernardo S
TI  - Nanobodies dismantle post‐pyroptotic ASC specks and counteract inflammation in vivo
JO  - EMBO molecular medicine
VL  - 14
IS  - 6
SN  - 1757-4676
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2026-00089
SP  - e15415
PY  - 2022
AB  - 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 (VHHASC ) target and disassemble post-pyroptotic inflammasomes, neutralizing their prionoid, and inflammatory functions. Notably, pyroptosis-driven membrane perforation and exposure of ASC specks to the extracellular environment allowed VHHASC to target inflammasomes while preserving pre-pyroptotic IL-1β release, essential to host defense. Systemically administrated mouse-specific VHHASC attenuated inflammation and clinical gout, and antigen-induced arthritis disease. Hence, VHHASC neutralized post-pyroptotic inflammasomes revealing a previously unappreciated role for these complexes in disease. VHHASC are the first biologicals that disassemble pre-formed inflammasomes while preserving their functions in host defense.
KW  - Animals
KW  - CARD Signaling Adaptor Proteins: metabolism
KW  - Caspase 1: metabolism
KW  - Humans
KW  - Inflammasomes: metabolism
KW  - Inflammation: metabolism
KW  - Mice
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - Pyroptosis
KW  - Single-Domain Antibodies
KW  - arthritis (Other)
KW  - extracellular inflammasomes (Other)
KW  - gout (Other)
KW  - nanobodies (Other)
KW  - pyroptosis (Other)
KW  - CARD Signaling Adaptor Proteins (NLM Chemicals)
KW  - Inflammasomes (NLM Chemicals)
KW  - NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
KW  - Single-Domain Antibodies (NLM Chemicals)
KW  - Caspase 1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
DO  - DOI:10.15252/emmm.202115415
UR  - https://pub.dzne.de/record/284081
ER  -