ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Endocytosis and non-canonical autophagy mediate extracellular histones cytotoxicity in vascular models of sepsis
Provisionally accepted
C Garcés1P Tascón1L Diago Domingo2A J Ibáñez1G Herrera1L R Rodríguez3K Salewskij4
Gustav Jonsson4J M Penninger4
Federico V Pallardó1*
Carlos Romá-Mateo1*- 1University of Valencia, Valencia, Spain
- 2Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
- 3Lunds universitet Lunds stamcellscentrum, Lund, Sweden
- 4Institut fur Molekulare Biotechnologie GmbH, Vienna, Austria
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Sepsis, a widespread global ailment, involves an exaggerated immune response, leading to hyperinflammation and immunosuppression. Extracellular histones, released during hyperinflammation as part of the defensive response against pathogens, significantly contribute to sepsis pathogenesis, compromising viability of the host's endothelial cells and contributing to organ failure. This study explores the link between cytotoxic effects of extracellular histones and endocytosis mechanisms in human umbilical vein endothelial cells (HUVECs) and blood vessel organoids (BVOs). Exposure to various doses of purified extracellular histones in both HUVECs cultures and BVOs revealed sub-lethal doses leading to histone entry and colocalization with the autophagy mediator LC3B, whereas high doses induced cytotoxicity. Incubating cells or organoids at low temperature before histone exposure prevented entry, reducing colocalization with LC3B and cell death; moreover, inhibition of clathrin-mediated endocytosis abrogated histone entry into HUVECs and prevented their cytotoxic effects, whereas inhibition of caveolin-mediated mechanisms had no effect. In conclusion, this study offers insights into histones' cytotoxicity and functional interactions with the LC3B-mediated, non-canonical autophagy pathway, enhancing our understanding of the molecular bases of sepsis pathophysiology within HUVEC and blood vessel organoids.
Keywords: Sepsis, Extracellular histones, Endocytosis, Non-canonical autophagy, HUVECs, blood vessel organoids, LC3B, LC3-associated endocytosis
Received: 20 Jun 2025; Accepted: 24 Nov 2025.
Copyright: © 2025 Garcés, Tascón, Diago Domingo, Ibáñez, Herrera, Rodríguez, Salewskij, Jonsson, Penninger, Pallardó and Romá-Mateo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Federico V Pallardó, federico.v.pallardo@uv.es
Carlos Romá-Mateo, carlos.roma@uv.es
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