ARF6 inhibition stabilizes the vasculature and enhances survival during endotoxic shock.
The vascular endothelium responds to infection by destabilizing endothelial cell-cell junctions to allow fluid and cells to pass into peripheral tissues, facilitating clearance of infection and tissue repair. During sepsis, endotoxin and other proinflammatory molecules induce excessive vascular leak, which can cause organ dysfunction, shock, and death. Current therapies for sepsis are limited to antibiotics and supportive care, which are often insufficient to reduce morbidity and prevent mortality. Previous attempts at blocking inflammatory cytokine responses in humans proved ineffective at reducing the pathologies associated with sepsis, highlighting the need for a new therapeutic strategy. The small GTPase ARF6 is activated by a MyD88-ARNO interaction to induce vascular leak through disruption of endothelial adherens junctions. In this study, we show that the MyD88-ARNO-ARF6-signaling axis is responsible for LPS-induced endothelial permeability and is a destabilizing convergence point used by multiple inflammatory cues. We also show that blocking ARF6 with a peptide construct of its N terminus is sufficient to reduce vascular leak and enhance survival during endotoxic shock, without inhibiting the host cytokine response. Our data highlight the therapeutic potential of blocking ARF6 and reducing vascular leak for the treatment of inflammatory conditions, such as endotoxemia.
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112; Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112;
Chadwick T
CT
Davis
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112;
Weiquan
W
Zhu
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112;
Christopher C
CC
Gibson
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112;
Jay A
JA
Bowman-Kirigin
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112;
Lise
L
Sorensen
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112;
Jing
J
Ling
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112; Department of Respiratory and Critical Care Medicine, Jinling Hospital, Clinical School of Nanjing University, Nanjing 210002, China;
Huiming
H
Sun
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112;
Sutip
S
Navankasattusas
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112; Department of Medicine, University of Utah, Salt Lake City, UT 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112; Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City, UT 84112; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China; and Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT 84112 dean.li@u2m2.utah.edu.
Dean Y
DY
Li
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000276:immunology*; D022005:Adherens Junctions / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
D000089982:ADP-Ribosylation Factor 6; D020690:GTPase-Activating Proteins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C102474:cytohesin-2; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse