Xiao Tsan Sam
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Immunol Rev. 2015 May;265(1):103-11. doi: 10.1111/imr.12281.
Inflammasomes are oligomeric signaling complexes that promote caspase activation and maturation of proinflammatory cytokines. Structural and biophysical studies have shed light on the mechanisms of nucleic acid recognition and signaling complex assembly involving the AIM2 (absent in myeloma 2) and IFI16 (γ-interferon-inducible protein 16) inflammasomes. However, our understanding of the mechanisms of the NLRP3 (nucleotide-binding oligomerization-like receptor family, pyrin domain-containing protein 3) activation, either by nucleic acids or by other reported stimuli, has remained elusive. Exciting recent progress on the filament formation by the ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) pyrin domain and the IFI16-double stranded DNA complex has established that the formation of higher order polymers is one of the general mechanisms for signaling platform assembly in innate immune system. The paradigm-changing discovery of the extracellular function of the NLRP3-ASC inflammasome has opened the door for therapeutic targeting the inflammasome filament formation for various clinical conditions. Future characterization of the canonical and non-canonical inflammasome complexes will undoubtedly reveal more surprises on their structure and function and enrich our understanding of the molecular mechanisms of ligand recognition, activation, and regulation.
炎性小体是促进半胱天冬酶激活和促炎细胞因子成熟的寡聚信号复合物。结构和生物物理研究揭示了涉及AIM2（骨髓瘤2中缺失）和IFI16（γ干扰素诱导蛋白16）炎性小体的核酸识别和信号复合物组装机制。然而，我们对NLRP3（含核苷酸结合寡聚化样受体家族、吡啉结构域蛋白3）通过核酸或其他报道的刺激物激活机制仍不清楚。最近关于含半胱天冬酶招募结构域的凋亡相关斑点样蛋白（ASC）吡啉结构域和IFI16双链DNA复合物形成细丝的激动人心的进展表明，高阶聚合物的形成是先天免疫系统中信号平台组装的一般机制之一。NLRP3-ASC炎性小体细胞外功能这一改变范式的发现为针对各种临床病症靶向炎性小体细丝形成进行治疗打开了大门。未来对经典和非经典炎性小体复合物的表征无疑将揭示更多关于其结构和功能的惊喜，并丰富我们对配体识别、激活和调节分子机制的理解。
