ABSTRACT
During inflammation, and depending upon cytokine microenvironment, tissue
resident and infiltrating macrophages can undergo polarisation towards a classically
activated phenotype (IFN-g, TNF, or LPS) or towards an alternatively activated phenotype (IL-4, IL-10, TGF-b 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.
