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. Notably, pyroptosis-driven membrane perforation and exposure of ASC specks to the extracellular environment allowed VHH_ASC to target inflammasomes while preserving pre-pyroptotic IL-1β release, essential to host defense. Systemically administrated mouse-specific VHH_ASC attenuated inflammation and clinical gout, and antigen-induced arthritis disease. Hence, VHH_ASC neutralized post-pyroptotic inflammasomes revealing a previously unappreciated role for these complexes in disease. VHH_ASC are the first biologicals that disassemble pre-formed inflammasomes while preserving their functions in host defense.

中文翻译：

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纳米抗体可消除焦亡后的 ASC 斑点并抵消体内炎症

炎症小体感知感染、损伤或代谢失衡的细胞内线索。激活的炎性体传感器将适配器 ASC 聚合成微米大小的“斑点”，以最大限度地激活 caspase-1 和 IL-1 细胞因子的成熟。Caspase-1 还驱动细胞焦亡，这是一种裂解细胞死亡，其特征是细胞内内容物泄漏到细胞外空间。ASC 斑点在细胞溶质中释放，并在慢性炎症患者的组织中积聚。然而，如果细胞外 ASC 斑点导致疾病，或者仅仅是细胞死亡的惰性残余物，仍然未知。在这里，我们展示了骆驼衍生的针对 ASC 的纳米抗体（VHH _ASC) 靶向并分解焦亡后炎症小体，中和它们的类朊病毒和炎症功能。值得注意的是，细胞焦亡驱动的膜穿孔和 ASC 斑点暴露于细胞外环境使 VHH _ASC能够靶向炎症小体，同时保持细胞焦亡前 IL-1β 的释放，这对宿主防御至关重要。全身给药的小鼠特异性 VHH _ASC可减轻炎症和临床痛风以及抗原诱导的关节炎疾病。因此，VHH _ASC中和了焦亡后炎症小体，揭示了这些复合物在疾病中的先前未被重视的作用。VHH _ASC是第一个分解预先形成的炎性体同时保留其在宿主防御中的功能的生物制品。