Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-10-01 Epub Date: 2025-09-08 DOI:10.1038/s44319-025-00558-7

Kathrin Krause, Sandra Franch Arroyo, Matteo Ugolini, Tonya Kueck, Timothy J Sullivan, Eric J C Gálvez, Matthias Muenzner, Christian Goosmann, Volker Brinkmann, Christian K Frese, Kathirvel Alagesan, Tim Vierbuchen, Holger Heine, Ulrike Resch, Leif E Sander, Emmanuelle Charpentier

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引用次数: 0

Abstract

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.

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化脓性链球菌EVs通过caspase-4/-5在人单核细胞中诱导替代炎性体。

在过去的十年里，先天免疫系统对革兰氏阴性细胞外囊泡（EVs）的感知得到了广泛的研究。相比之下，先天免疫细胞对革兰氏阳性ev的识别仍然知之甚少。对人类单核细胞的比较全基因组转录分析发现，化脓性葡萄球菌EVs诱导的促炎特征与亲本细胞明显不同。在ev特异性上调的209个基因中，caspase-5促使我们深入研究炎症小体信号通路。我们发现，脂质磷壁酸（LTA）是存在于化脓性葡萄球菌和其他革兰氏阳性菌EVs上的革兰氏阳性菌膜的结构成分，它被TLR2感知，从而触发由NLRP3和炎性caspase -4/-5组成的替代炎性体，在不诱导细胞死亡的情况下产生IL-1β反应。对于化脓性链球菌，我们发现TLR8是介导caspase-4/-5依赖性IL-1β分泌的传感器。值得注意的是，在单核细胞中，完整细菌的炎性小体激活与全局毒力调节因子冠状病毒无关。总之，我们的研究强调了TLR2和caspase-4/-5在人单核细胞中识别革兰氏阳性ev中的新作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.