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Gemma Beers, Joanne Boldison, David Alexander Copland, Peter S Adamson, Lindsay B Nicholson, Andrew D Dick; Characterising the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in experimental autoimmune uveoretinitis (EAU). Invest. Ophthalmol. Vis. Sci. 2014;55(13):2500. doi: https://doi.org/.
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Macrophage activation can be regulated via hydrolysis of oxidised low density lipoproteins (oxLDL) by Lp-PLA2. This produces lysophosphatidylcholine and non-esterified fatty acids that up-regulate expression of chemokines and adhesion molecules, induce macrophage migration and promote pro-inflammatory cytokine release. Inhibition of this enzyme may therefore perturb macrophage function and attenuate inflammation. We utilised Lp-PLA2 knockout (KO) mice to determine the effect of Lp-PLA2 depletion in autoimmune retinal inflammation, employing a murine model of autoimmune uveitis, EAU, in which macrophages are central to progression and expression of disease. Uveitis is a prominent cause of visual impairment, found commonly in the working age population. As such, research into the underlying mechanisms of the disease and development of new treatment options is important to overcome the medical, social and financial implications associated with this pathology.
C57BL/6 Lp-PLA2 KO mice, heterozygotes (HET) and wild type (WT) controls were immunized to induce EAU by subcutaneous injection of RBP-3 (IRBP)1-20 peptide in Complete Freund’s adjuvant, plus intra-peritoneal (IP) injection of heat inactivated pertussis toxin. Clinical disease was monitored by Topical Endoscopic Fundus imaging (TEFI). Mice were sacrificed on day 26 post immunisation, infiltrating leukocytes were quantified by flow cytometry and histological disease severity was assessed.
Lp-PLA2 KO mice showed substantially fewer infiltrating CD45+ cells compared to both WT and HET controls, which correlated with a lower disease score by TEFI and histology. In addition to a reduction in the absolute number of infiltrating cells in the retina, KO mice also exhibited an altered ratio of leukocyte populations compared to HET and WT controls. An apparent reduction in the number of CD4+ infiltrating cells in Lp-PLA2 KO retina may indicate an effect on T cell priming and subsequent tissue infiltration in these animals.
Lp-PLA2 KO mice, immunised to induce EAU experienced decreased macrophage infiltration and less clinical disease. The observation of suppressed clinical and histological disease score and number of infiltrating cells infers a reduction in both activation and migration of inflammatory cells via depletion of Lp-PLA2.
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