Nanobodies dismantle post‐pyroptotic ASC specks and counteract inflammation in vivo

Nanobodies dismantle post‐pyroptotic ASC specks and counteract inflammation in vivo

Abstract 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 d...

Full description

Bibliographic Details
Main Authors: Damien Bertheloot, Carlos WS Wanderley, Ayda H Schneider, Lisa DJ Schiffelers, Jennifer D Wuerth, Jan MP Tödtmann, Salie Maasewerd, Ibrahim Hawwari, Fraser Duthie, Cornelia Rohland, Lucas S Ribeiro, Lea‐Marie Jenster, Nathalia Rosero, Yonas M Tesfamariam, Fernando Q Cunha, Florian I Schmidt, Bernardo S Franklin
Format: Article
Language:English
Published: Springer Nature 2022-06-01
Series:EMBO Molecular Medicine
Subjects:
arthritis
extracellular inflammasomes
gout
nanobodies
pyroptosis
Online Access:https://doi.org/10.15252/emmm.202115415
Description
Summary:Abstract 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.
ISSN:1757-4676
1757-4684

Similar Items