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

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE. Caveolin-1 (Cav-1), the signature protein of caveolae, modulates inflammatory responses, and innate immunity. However, Cav-1́s 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.

METHODS. 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.

CONCLUSIONS. 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.

RESULTS. 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.

Original languageEnglish (US)
Pages (from-to)6224-6234
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number10
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Blood–retinal barrier
  • Caveolin
  • Cytokines
  • Inflammation

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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