ASC-expressing pyroptotic extracellular vesicles alleviate sepsis by protecting B cells

• Published in: Molecular therapy Vol. 32; no. 2; pp. 395 - 410
• Main Authors: Huang, Weiying, Wang, Ben, Ou, Qianmin, Zhang, Xiao, He, Yifan, Mao, Xueli, Wei, Xi, Kou, Xiaoxing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2024
• Subjects: apoptosis-associated speck-like protein containing CARD; B cells; mesenchymal stem cells; pyroptosis; pyroptotic extracellular vesicles; sepsis; pyroptotic extracellular vesicles; pyroptosis; apoptosis-associated speck-like protein containing CARD; B cells; mesenchymal stem cells; sepsis
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2023.12.008

Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated extracellular vesicles (EVs) are largely unknown. Here, we identified a group of pyroptotic EVs (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs), as well as from septic mouse blood. Compared with apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers, but express a decreased level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing Toll-like receptor 4. This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response. [Display omitted] Kou and colleagues identified a new group of pyroEVs and revealed their therapeutic effect on sepsis. Specific expression of ASC can serve as a marker and mediate pyroEV binding to the surface of B cells to reduce B cell death via repressing the Toll-like receptor 4 (TLR4) pathway.