Abstract
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.
Footnotes
C.T.D. and D.Y.L. were responsible for project conceptualization, data analysis, and manuscript preparation. C.T.D., W.Z., C.C.G., J.B.-K., L.S., J.L., H.S., S.N., and D.Y.L. were responsible for assay design and data collection. D.Y.L. was responsible for funding the project.
This work was supported by the National Institutes of Health, the American Heart Association, the H.A. and Edna Benning Foundation, the Juvenile Diabetes Research Foundation, and the Burroughs Wellcome Fund (to D.Y.L.).
Abbreviations used in this article:
- DD
- death domain
- EEA1
- early endosome Ag 1
- HBSS/A
- HBSS supplemented with 1% human serum albumin
- HMVEC-D
- human dermal microvascular endothelial cell
- ID
- intermediate domain
- PMN
- polymorphonuclear leukocyte
- siRNA
- small interfering RNA
- TIR
- Toll/IL-1R
- VE-cadherin
- vascular endothelial cadherin.
- Received January 31, 2014.
- Accepted April 16, 2014.
- Copyright © 2014 by The American Association of Immunologists, Inc.