Nitric oxide in experimental autoimmune uveoretinitis

During inflammation, and depending upon cytokine microenvironment, tissue resident and infiltrating macrophages can undergo polarisation towards a classically activated phenotype (IFN-γ, TNF, or LPS) or towards an alternatively activated phenotype (IL-4, IL-10, TGF-β or PGE₂). Classically activated macrophages drive increased intensity of inflammation associated with Th1 driven cellular responses and nitric oxide driven tissue damage whilst alternatively activated macrophages mediate Th2 cell differentiation, tolerance induction, down regulation of inflam- mation and healing. These opposing functional effects are controlled by cytokine or other polarising factors. Driving the balance towards an alternatively activated, healing phenotype is crucial to re-establish tissue homeostasis and disease remis- sion. We have used rodent models to explore the role of macrophages in experi- mental autoimmune uveoretinitis (EAU), and how their function might be manipulated to limit retinal damage. In the normal CNS and retina, tissue resident macrophages and myeloid cells appear to be polarised towards alternatively acti- vated phenotype, and this polarisation appears irreversible, providing a regulatory mechanism within the tissue that is over-ridden during autoimmune inflammation. Infiltrating classically activated monocyte-macrophages are essential for full expression of disease and our histological and trafficking experiments indicate that they are amongst the first cells to infiltrate the retina and may be the key cells initiating blood retina barrier breakdown. Infiltrating macrophages that are re- activated locally by T cell derived cytokines are also primary effectors of photo- receptor damage through nitric oxide and super-oxide generation but show greater resistance to apoptosis during EAU than would otherwise expected under normal inflammatory conditions, due to expression of a caspase 8 inhibitory molecule, FLIP. Down regulation of these classically activated macrophages through altering the cytokine microenvironment is key to controlling inflammation.