The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis.
Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a r...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0122093 |
| _version_ | 1819032688199204864 |
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| author | G L Crawford J Boldison D A Copland P Adamson D Gale M Brandt L B Nicholson A D Dick |
| author_facet | G L Crawford J Boldison D A Copland P Adamson D Gale M Brandt L B Nicholson A D Dick |
| author_sort | G L Crawford |
| collection | DOAJ |
| description | Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity. |
| first_indexed | 2024-12-21T07:05:55Z |
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| id | doaj.art-ce888cb2f4b34c2e96e00eca95e627a0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T07:05:55Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ce888cb2f4b34c2e96e00eca95e627a02022-12-21T19:12:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012209310.1371/journal.pone.0122093The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis.G L CrawfordJ BoldisonD A CoplandP AdamsonD GaleM BrandtL B NicholsonA D DickMacrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity.https://doi.org/10.1371/journal.pone.0122093 |
| spellingShingle | G L Crawford J Boldison D A Copland P Adamson D Gale M Brandt L B Nicholson A D Dick The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis. PLoS ONE |
| title | The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis. |
| title_full | The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis. |
| title_fullStr | The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis. |
| title_full_unstemmed | The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis. |
| title_short | The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis. |
| title_sort | role of lipoprotein associated phospholipase a2 in a murine model of experimental autoimmune uveoretinitis |
| url | https://doi.org/10.1371/journal.pone.0122093 |
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