Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Immunity. 2010 Mar 26;32(3):379-91. doi: 10.1016/j.immuni.2010.03.003. Epub 2010 Mar 18.
Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn's disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1beta (IL-1beta) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.
Nlrp3 蛋白表达降低与克罗恩病易感性相关。然而，Nlrp3 在结肠炎中的作用尚未被阐明。Nlrp3 与衔接蛋白 ASC 相互作用，在炎症小体中激活半胱天冬酶-1，炎症小体是负责白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）成熟和分泌的蛋白复合物。在这里，我们发现 Nlrp3、ASC 和半胱天冬酶-1 缺失的小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎高度敏感。炎症小体激活缺陷导致上皮完整性丧失，导致共生细菌在全身扩散，大量白细胞浸润，以及结肠中趋化因子的产生增加。这个过程是由于缺乏 Nlrp3 炎症小体成分的小鼠中 IL-18 减少所致，导致死亡率更高。因此，Nlrp3 炎症小体在维持肠道内稳态和防止结肠炎方面起着至关重要的作用。
