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Y. de Kozak, M.–C. Naud, B. Thillaye–Goldenberg, A. Nardin; Prevention of Endotoxin–Induced Uveitis (EIU) by Macrophage Activation . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2917.
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© ARVO (1962-2015); The Authors (2016-present)
EIU is a model of human ocular inflammation that appears in Reiter’s, Crohn’s and Behcet’s diseases. The aim of this work is to test the effect on LPS–induced ocular inflammation of the monocyte activator muramyl tripeptide phosphatidylethanolamine (MTP–PE). To increase its efficiency and preferential targetting in monocytes, MTP–PE was encapsulated in liposomes (L–MTP–PE).
EIU was induced in Lewis rats by one footpad injection of LPS (350–500 ug/kg) from gram negative bacteria. As a treatment, L–MTP–PE were injected intravitreally (IVT) (1ug/10ul of saline) 7 days before LPS injection. Control rats received IVT injection of either saline+LPS, empty liposomes+LPS or empty liposomes. Rats were observed clinically at slit lamp and were sacrificed 24 h after LPS injection. Immunohistochemistry was performed on cryostat sections using antibodies specific for ED1,TLR4, NOS–2. Cytokine mRNA expression (TNF–a, NOS–2, MCP–1, IL–1b, IL–6, IL–12p40, TGF–b, IL–10) was detected by RT–PCR.
Empty liposomes injected in a normal eye did not induce inflammation. Twenty four hours after LPS injection, time of maximal severity in controls, a significant clinical inhibition of ocular inflammation was observed in rats injected with L–MTP–PE compared to controls. By immunohistochemistry, control rats showed strong TLR4 expression in iris/ciliary body with important expression of NOS–2 in inflammatory cells. In L–MTP–PE–injected rats, diminished expression of TLR4 was observed in iris/cilary body with reduction of the number of PMNs and increase of ED1+ macrophage infiltration in iris–ciliary body and retina. Macrophages were TLR4 negative, NOS–2 negative. Compared to control rats, a significantly reduced mRNA expression of TNF–a, NOS–2, MCP–1 and Th1 cytokines (IL–1b, IL–6, IL–12p40) was observed in eyes from rats injected with L–MTP–PE contrasting with an increased expression of Th2 cytokine (TGF–b, IL–10).
Our results provide evidence for the role of macrophages in the regulation of ocular inflammation. L–MTP–PE treatment allowed to increase the number of macrophages in iris/ciliary body and retina. A decreased intraocular expression of NOS–2, TNF–a and Th1 cytokine mRNAs was observed whereas Th2 cytokines were upregulated. These results suggest that the treatment activated intraocular macrophages and confered them a polarized M2 phenotype. The local administration of L–MTP–PE may be of great benefit for the prevention of uveitis through regulation of Th1 and Th2 polarized immune response.
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