Department of Immunology, UConn Health School of Medicine, Farmington, CT, USA.
National Institute of Biological Sciences, Beijing, China.
Nat Immunol. 2019 May;20(5):527-533. doi: 10.1038/s41590-019-0368-3. Epub 2019 Apr 8.
Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called 'pyroptosis', which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions.
固有免疫系统通过监测细胞溶质区室中的病原体编码产物或病原体活性，通常能够激活一组半胱天冬酶。在大多数情况下，细胞溶质监测途径与通过经典炎症小体复合物激活 caspase-1 相关联。一组相关的半胱天冬酶，即啮齿动物中的 caspase-11 和人类中的 caspase-4 和 caspase-5，监测细胞溶质中的细菌脂多糖 (LPS)。细胞内 LPS 直接激活 caspase-11、caspase-4 和 caspase-5 会引发称为“细胞焦亡”的溶细胞性死亡，这种死亡发生在多种细胞类型中。细胞焦亡由孔形成蛋白 GSDMD 执行，该蛋白通过 caspase-11、caspase-4 或 caspase-5 介导的切割而被激活。在单核细胞中，GSDMD 孔的形成可以诱导 NLRP3 炎症小体的激活，从而成熟细胞因子 IL-1β 和 IL-18。针对细胞溶质 LPS 的 caspase-11 介导的细胞焦亡对于抗菌防御和感染性休克至关重要。本文综述了关于细胞溶质 LPS 及其调控和病理生理功能的新兴文献。
