Oncostatin M-driven leak in human endothelial cells with preserved tight junctions
Abstract
Blood vessels must preserve blood volume while permitting exchange of nutrients. Endothelial cells line the lumen of all blood vessels and form the intercellular junctions that govern vascular permeability. In acute critical illness the barrier fails, fluid escapes into tissues, and the resulting loss of volume and impaired nutrient exchange cause organ failure. Several inflammatory cytokines are known to disrupt junctions in cultured cells, yet therapies targeting these models have failed. How blood vessels respond to critical illness has remained largely elusive because endothelial cells are generally inaccessible. Here we profile endothelial cells recovered directly from critically ill children to show that oncostatin M drives a previously unrecognized mode of vascular leak. Oncostatin M increases permeability by forming narrow, nanoscale channels within the overlapping borders of adjacent cells, around intact tight junctions. These channels permit passage of small and intermediate sized solutes. Their formation depends on non-canonical signaling in which the kinase JAK1 activates two required parallel pathways (via ERK1 and AKT1) that converge on the transcription factor c-Fos. Inhibiting JAK1, either parallel pathway or depleting c-Fos, prevents oncostatin M-induced loss of barrier function. These results identify a permeability mechanism distinct from the junction disassembly driven by the cytokines that have dominated this field and implicate kinases already targeted by approved drugs as potential points of intervention. More broadly, vascular barriers are transiently loosened during immune-cell trafficking and metastasis, raising the possibility that diverse forms of vascular permeability arise through regulated nanoscale remodeling rather than junctional breakdown.
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BibTeX
@misc{fulgoni2026oncostatin,
title = {{Oncostatin M-driven leak in human endothelial cells with preserved tight junctions}},
author = {Giulio Fulgoni and Francesc López-Giráldez and Zenaat Malik and Guilin Wang and Elena Wilson and Clancy W Mullan and Weiming Ni and Xinran Nick Liu and Feng-Xia Liang and C. Shan Xu and Song Pang and E. Vincent S. Faustino and Jordan S. Pober and Richard W. Pierce},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761942},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761942v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Oncostatin M-driven leak in human endothelial cells with preserved tight junctions
AU - Giulio Fulgoni
AU - Francesc López-Giráldez
AU - Zenaat Malik
AU - Guilin Wang
AU - Elena Wilson
AU - Clancy W Mullan
AU - Weiming Ni
AU - Xinran Nick Liu
AU - Feng-Xia Liang
AU - C. Shan Xu
AU - Song Pang
AU - E. Vincent S. Faustino
AU - Jordan S. Pober
AU - Richard W. Pierce
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761942
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761942v1
AB - Blood vessels must preserve blood volume while permitting exchange of nutrients. Endothelial cells line the lumen of all blood vessels and form the intercellular junctions that govern vascular permeability. In acute critical illness the barrier fails, fluid escapes into tissues, and the resulting loss of volume and impaired nutrient exchange cause organ failure. Several inflammatory cytokines are known to disrupt junctions in cultured cells, yet therapies targeting these models have failed. How blood vessels respond to critical illness has remained largely elusive because endothelial cells are generally inaccessible. Here we profile endothelial cells recovered directly from critically ill children to show that oncostatin M drives a previously unrecognized mode of vascular leak. Oncostatin M increases permeability by forming narrow, nanoscale channels within the overlapping borders of adjacent cells, around intact tight junctions. These channels permit passage of small and intermediate sized solutes. Their formation depends on non-canonical signaling in which the kinase JAK1 activates two required parallel pathways (via ERK1 and AKT1) that converge on the transcription factor c-Fos. Inhibiting JAK1, either parallel pathway or depleting c-Fos, prevents oncostatin M-induced loss of barrier function. These results identify a permeability mechanism distinct from the junction disassembly driven by the cytokines that have dominated this field and implicate kinases already targeted by approved drugs as potential points of intervention. More broadly, vascular barriers are transiently loosened during immune-cell trafficking and metastasis, raising the possibility that diverse forms of vascular permeability arise through regulated nanoscale remodeling rather than junctional breakdown.
SN - 2692-8205
ER -