Krause Kathrin, Franch Arroyo Sandra, Ugolini Matteo, Kueck Tonya, Sullivan Timothy J, Gálvez Eric J C, Muenzner Matthias, Goosmann Christian, Brinkmann Volker, Frese Christian K, Alagesan Kathirvel, Vierbuchen Tim, Heine Holger, Resch Ulrike, Sander Leif E, Charpentier Emmanuelle
Max Planck Unit for the Science of Pathogens, Berlin, D-10117, Germany.
Institute for Biology, Humboldt University, Berlin, D-10115, Germany.
EMBO Rep. 2025 Sep 8. doi: 10.1038/s44319-025-00558-7.
The sensing of Gram-negative Extracellular Vesicles (EVs) by the innate immune system has been extensively studied in the past decade. In contrast, recognition of Gram-positive EVs by innate immune cells remains poorly understood. Comparative genome-wide transcriptional analysis in human monocytes uncovered that S. pyogenes EVs induce proinflammatory signatures that are markedly distinct from those of their parental cells. Among the 209 genes exclusively upregulated by EVs, caspase-5 prompted us to study inflammasome signaling pathways in depth. We show that lipoteichoic acid (LTA), a structural component of Gram-positive bacterial membranes present on EVs from S. pyogenes and other Gram-positive species, is sensed by TLR2 which triggers the alternative inflammasome composed of NLRP3 and the inflammatory caspases-4/-5 to mount an IL-1β response without inducing cell death. For S. pyogenes, we identify TLR8 as a sensor to mediate caspase-4/-5-dependent IL-1β secretion. Notably, inflammasome activation by intact bacteria is independent of the global virulence regulator CovS in monocytes. Overall, our study highlights a new role for TLR2 and caspase-4/-5 in the recognition of Gram-positive EVs in human monocytes.
在过去十年中，天然免疫系统对革兰氏阴性细胞外囊泡（EVs）的感知已得到广泛研究。相比之下，天然免疫细胞对革兰氏阳性EVs的识别仍知之甚少。对人类单核细胞进行的全基因组转录比较分析发现，化脓性链球菌EVs诱导的促炎特征与其亲本细胞的特征明显不同。在仅由EVs上调的209个基因中，半胱天冬酶-5促使我们深入研究炎性小体信号通路。我们发现，脂磷壁酸（LTA）是化脓性链球菌和其他革兰氏阳性菌的EVs上存在的革兰氏阳性细菌膜的一种结构成分，可被TLR2感知，TLR2触发由NLRP3和炎性半胱天冬酶-4/-5组成的替代性炎性小体，引发IL-1β反应而不诱导细胞死亡。对于化脓性链球菌，我们确定TLR8作为一种传感器来介导半胱天冬酶-4/-5依赖性IL-1β分泌。值得注意的是，完整细菌激活炎性小体与单核细胞中的全局毒力调节因子CovS无关。总体而言，我们的研究突出了TLR2和半胱天冬酶-4/-5在人类单核细胞识别革兰氏阳性EVs中的新作用。
