dc.contributor.author |
Mugisho, Odunayo |
en |
dc.contributor.author |
Green, Colin |
en |
dc.contributor.author |
Kho, Dan |
en |
dc.contributor.author |
Zhang, Jie |
en |
dc.contributor.author |
Graham, Euan |
en |
dc.contributor.author |
Acosta Etchebarne, Monica |
en |
dc.contributor.author |
Rupenthal, Ilva |
en |
dc.date.accessioned |
2018-12-03T03:40:05Z |
en |
dc.date.issued |
2018-03 |
en |
dc.identifier.issn |
0304-4165 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/44804 |
en |
dc.description.abstract |
Connexin43 hemichannels have been implicated in many inflammatory diseases including diabetic retinopathy (DR). Particularly, hemichannel-mediated ATP release has been associated with inflammasome pathway activation. Using an in vitro cell culture model, we evaluated hemichannel roles in response to inflammatory cytokines under high glucose (HG) conditions and propose a mechanism by which a connexin43 hemichannel-mediated autocrine ATP feedback loop augments chronic inflammatory disease.Retinal pigment epithelial cells were exposed to HG, 10ng/mL pro-inflammatory cytokines IL-1β and TNF-α, or a combination of both. Quantitative Cytometric Bead Array analysis was used to measure the release of inflammatory cytokines IL-6, IL-8, MCP-1, and sICAM-1, as well as VEGF and ATP. To determine the role of connexin43 hemichannels in the disease process, changes in cytokine and ATP release were evaluated following treatment with Peptide5, a connexin43 hemichannel blocker. Immunohistochemistry was used to compare NLRP3 inflammasome assembly under control and treatment conditions.Co-application of HG and cytokines increased the secretion of IL-6, IL-8, MCP-1, sICAM-1, VEGF and ATP, to significantly higher levels compared to cytokines alone. Peptide5 prevented cytokine release and prevented the increase in ATP release following co-application of HG and cytokines. Adding exogenous ATP negated Peptide5-mediated protection against inflammatory cytokine release in injury conditions.Our findings show that connexin43 hemichannels play an important role in the amplification and perpetuation of inflammation by mediating an ATP autocrine feedback loop in the inflammasome/inflammation cycle.Targeting connexin43 hemichannels offers a potential therapeutic strategy to break the inflammatory cycle in diseases such as DR, but also other chronic inflammatory indications. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Biochimica et biophysica acta. General subjects |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Cell Line |
en |
dc.subject |
Gap Junctions |
en |
dc.subject |
Epithelial Cells |
en |
dc.subject |
Humans |
en |
dc.subject |
Diabetic Retinopathy |
en |
dc.subject |
Hyperglycemia |
en |
dc.subject |
Inflammation |
en |
dc.subject |
Glucose |
en |
dc.subject |
Vascular Endothelial Growth Factor A |
en |
dc.subject |
Connexin 43 |
en |
dc.subject |
Adenosine Triphosphate |
en |
dc.subject |
Cytokines |
en |
dc.subject |
Autocrine Communication |
en |
dc.subject |
Retinal Pigment Epithelium |
en |
dc.subject |
Inflammasomes |
en |
dc.title |
The inflammasome pathway is amplified and perpetuated in an autocrine manner through connexin43 hemichannel mediated ATP release. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1016/j.bbagen.2017.11.015 |
en |
pubs.issue |
3 |
en |
pubs.begin-page |
385 |
en |
pubs.volume |
1862 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
29158134 |
en |
pubs.end-page |
393 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
718106 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Molecular Medicine |
en |
pubs.org-id |
Optometry and Vision Science |
en |
pubs.org-id |
School of Medicine |
en |
pubs.org-id |
Ophthalmology Department |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1872-8006 |
en |
pubs.record-created-at-source-date |
2017-11-22 |
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pubs.dimensions-id |
29158134 |
en |