biostudies-literatureUnknown26(19)Krause KDeutsche ForschungsgemeinschaftMax Planck SocietyTang Prize FoundationLouis-Jeantet FoundationThe 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 tEMBO reports4847-4885https://www.ebi.ac.uk/biostudies/studies/S-EPMC12508482biostudies-literatureStreptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.PMC12508482Resch UBrinkmann VAlagesan KVierbuchen TGoosmann CFrese CKUgolini MKueck TMuenzner MKrause KCharpentier EFranch Arroyo SSullivan TJGalvez EJCHeine HSander LEfalseStreptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.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 t2025-01-01T00:00:00Z2025 Oct2026-07-15T14:34:27.242Z2026-07-06T03:08:44.314ZS-EPMC125084824092595710.1038/s44319-025-00558-7