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Content archived on 2024-05-29

The role of the innate immune system in microglia activation and the priming of myelin-specific autoreactive T cells

Final Activity Report Summary - MGLIADIFF (The role of the innate immune system in microglia activation and the priming of myelin-specific autoreactive T cells)

Microglia are considered as the cells most capable of antigen presentation in the central nervous system (CNS), and are often referred to as the macrophages of the brain. Under homeostatic conditions, microglia appear to be resting and might even be actively suppressed by the brain microenvironment. Under inflammatory conditions like multiple sclerosis, microglia transform into cells that display characteristics of professional antigen-presenting cells (APC). This transformation process probably involves multiple steps and the outcome will be determined by the differentiation status of the microglia involved and by the mode of activation.

The differentiation of microglia is subject of intense research. Recent studies have demonstrated that when primary microglia obtained from fetal mice are subjected to different differentiation regimes this leads to the outgrowth of different populations of non-activated cell types. Such studies were not undisputed since the plasticity of microglia could also be explained by the fetal nature of the post mortem material.

Differentiation of microglia into different cell types could well influence the activation process of microglia-derived non-professional APC into professional APC. Toll-like receptors (TLR) are a family of receptors (for humans currently containing 10 different members) that have a central role in linking activation of the innate immune system to activation of the adaptive immune system. TLR ligands include microbiological cell surface and breakdown products, and TLR-TLRligand interactions in general provide a strong activating signal to the cell.

In order to study the transformation process of microglia into professional APC and to avoid the pitfalls of working with fetal material, we choose to set up in vitro methods in which microglia were derived from adult rhesus monkey brain material. Here we demonstrate that such microglia are indeed responsive to different differentiation regimes (in this case exposure to M-CSF or GM-CSF). In contrast to the fetal mouse data, we did not generate subpopulations of cells that could be clearly characterised as macrophages or immature dendritic cells respectively. Rhesus microglia subjected to either differentiation regime were CD45+, CD14+, CD11b+, CD11c-, and could therefore be characterised as macrophage-like. However, LPS-induced activation of GM-CSF differentiated microglia induced the stable expression of CD83, which is considered to be a dendritic cell marker. Most important differences between M-CSF and GM-CSF-differentiated microglia were found in the expression levels of molecules implicated in antigen presentation. In addition, we demonstrate that M-CSF differentiated microglia expressed higher mRNA levels of TLR1, 5, 7 and 8 as GM-CSF-differentiated microglia, whereas GM-CSF-differentiated microglia expressed higher levels of TLR3. mRNA levels for TLR2 and 4 were similar, whereas expression levels of TLR6, 9 and 10 were so low that it interfered with reliable quantification.

Preliminary data indicate that these differences might also have functional consequences for TLR-induced activation of these different subpopulations. Finally, we demonstrate that neither M-CSF nor GM-CSF differentiated rhesus microglia were responsive to TLR9-mediated activation. This is in line with our data on the mRNA expression levels of TLR9 and marks an important difference between non-human primates and rodents. In mice, TLR9-mediated signalling activates microglia, a response that appears absent in the CNS of primates.