Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation

Xiaoman Li; Xiaowu Gu; Timothy M Boyce; Min Zheng; Alaina M Reagan; Hui Qi; Nawajes Mandal; Alex W Cohen; Michelle C Callegan; Daniel J J Carr; Michael H Elliott

doi:10.1167/iovs.14-14613

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Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation

Journal article

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Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation

Xiaoman Li, Xiaowu Gu, Timothy M Boyce, Min Zheng, Alaina M Reagan, Hui Qi, Nawajes Mandal, Alex W Cohen, Michelle C Callegan, Daniel J J Carr, …

Investigative ophthalmology & visual science, Vol.55(10), pp.6224-6234

08/26/2014

DOI: 10.1167/iovs.14-14613

PMCID: PMC4183075

PMID: 25159208

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https://doi.org/10.1167/iovs.14-14613View

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Abstract

Caveolin-1 (Cav-1), the signature protein of caveolae, modulates inflammatory responses, and innate immunity. However, Cav-1's role in retinal inflammation has not been rigorously tested. In this study, we examined the effect of Cav-1 ablation on the sensitivity of the retina to inflammation. Cav-1 knockout (KO) mice were challenged by intravitreal injection of lipopolysaccharide (LPS) and inflammatory cell recruitment was assessed by flow cytometry and immunohistochemistry. Leukostasis was assessed in retinal flatmounts after perfusion with FITC-labeled Concanavalin A (FITC-ConA). Chemoattractants were measured by multiplex immunoassays. Blood-retinal barrier (BRB) breakdown was assessed quantitatively by a FITC-dextran permeability assay. The ratio of extravascular to total immune cells was determined by CD45 immunohistochemistry of retinal flatmounts. Inflammatory challenge resulted in significant blunting of proinflammatory cytokine (monocyte chemoattractant protein-1 [MCP-1/CCL2], CXCL1/KC, IL-6, and IL-1β) responses as well as reduced inflammatory BRB breakdown in Cav-1 KO retinas. Paradoxically, Cav-1 deficiency resulted in significantly increased recruitment of immune cells compared with controls as well as increased leukostasis. A similar ratio of extravascular/total leukocytes were found in Cav-1 KO and wild-type (WT) retinas suggesting that Cav-1 deficient leukocytes were as competent to extravasate as those from WT mice. We found increased levels of circulating immune cells in naïve (not challenged with LPS) Cav-1 KO mice compared with controls. Caveolin-1 paradoxically modulates inflammatory signaling and leukocyte infiltration through distinct mechanisms. We hypothesize that Cav-1 expression may enhance inflammatory signaling while at the same time supporting the physical properties of the BRB.

Flow Cytometry

Immunohistochemistry

Animals

Blood-Retinal Barrier - physiology

Blotting, Western

Caveolin 1 - biosynthesis

Caveolin 1 - genetics

Chemotactic Factors - metabolism

Disease Models, Animal

Gene Expression Regulation

Immunity, Innate - genetics

Leukocytes - immunology

Leukocytes - pathology

Mice

Mice, Inbred C57BL

Mice, Knockout

Real-Time Polymerase Chain Reaction

RNA - genetics

Uveitis - genetics

Uveitis - immunology

Uveitis - metabolism

Details

Title: Subtitle: Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation
Creators: Xiaoman Li - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Xiaowu Gu - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Timothy M Boyce - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Min Zheng - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Alaina M Reagan - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Hui Qi - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Nawajes Mandal - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Alex W Cohen - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Michelle C Callegan - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Daniel J J Carr - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Michael H Elliott - Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.55(10), pp.6224-6234
DOI: 10.1167/iovs.14-14613
PMID: 25159208
PMCID: PMC4183075
ISSN: 0146-0404
eISSN: 1552-5783
Grant note: P30 EY021725 / NEI NIH HHS EY019494 / NEI NIH HHS EY012985 / NEI NIH HHS R01 EY019494 / NEI NIH HHS EY022071 / NEI NIH HHS EY024140 / NEI NIH HHS R01 EY024140 / NEI NIH HHS P30EY021725 / NEI NIH HHS R01 EY021238 / NEI NIH HHS EY021238 / NEI NIH HHS R01 EY012985 / NEI NIH HHS R01 EY022071 / NEI NIH HHS
Language: English
Date published: 08/26/2014
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9984172168102771

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