Journal
EMBO MOLECULAR MEDICINE
Volume 14, Issue 6, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202115415
Keywords
arthritis; extracellular inflammasomes; gout; nanobodies; pyroptosis
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [388158066, 216372545, 388159768]
- European Research Council [PLAT-IL-1 714175]
- Germany's Excellence Strategy from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [EXC 2151 - 390873048]
- DFG [EXC 2151 - 390873048, 322568668, TRR237-369799452]
- Medical Faculty of the University of Bonn
- Projekt DEAL
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Inflammasomes are activated by intracellular clues and play important roles in cell death and inflammation. This study demonstrates that a specific antibody can neutralize activated inflammasomes and alleviate inflammatory diseases.
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-1 beta 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.
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