Friday, 23 December 2011

Research: Damaging Microglia

Huizinga R, van der Star BJ, Kipp M, Jong R, Gerritsen W, Clarner T, Puentes F, Dijkstra CD, Valk PV, Amor S. Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis. Glia. 2011 . doi: 10.1002/glia.22276. [Epub]

Neuroaxonal degeneration is a pathological hallmark of multiple sclerosis (MS) contributing to irreversible neurological disability. Pathological mechanisms leading to axonal damage include autoimmunity to neuronal antigens.

In actively demyelinating lesions, myelin is phagocytosed by microglia and blood-borne macrophages, whereas the fate of degenerating or damaged axons is unclear. Phagocytosis (engulfing by cells such as macrophages) is essential for clearing neuronal debris to allow repair and regeneration. However, phagocytosis may lead to antigen presentation and autoimmunity, as has been described for neuroaxonal antigens. Despite this notion, it is unknown whether phagocytosis of neuronal antigens occurs in MS.

Here, we show using novel, well-characterized antibodies to axonal antigens, that axonal damage is associated with HLA-D/ MHC class II (a protien that is used to activate T cells) expressing microglia/macrophages engulfing axonal bulbs, indicative of axonal damage. Neuronal proteins were frequently observed inside HLA-DR(+) cells in areas of axonal damage. In vitro, phagocytosis of neurofilament light (NF-L. A nerve scaffolding protein), present in white and gray matter, was observed in human microglia. The number of NF-L or myelin basic protein (MBP) positive cells was quantified using the mouse macrophage cell line J774.2. Intracellular colocalization of NF-L with the lysosomal membrane protein LAMP1 was observed using confocal microscopy confirming that NF-L is taken up and degraded by the cell. In vivo, NF-L and MBP was observed in cerebrospinal fluid cells from patients with MS, suggesting neuronal debris is drained by this route after axonal damage.

In summary, neuroaxonal debris is engulfed, phagocytosed, and degraded by HLA-DR(+) cells. Although uptake is essential for clearing neuronal debris, phagocytic cells could also play a role in augmenting autoimmunity to neuronal antigens.

Axonal bulb in MS occurs when axons are cut and molecules being transported down the axon accumulate in the bulb. Abit like a ballooon blowing-up as air is pushed down the spout.

We know that microglia and macrophages are vital in clearing up the debris that occurs during attack. This is important for repair and remyelination and there appearto be good-microglia. But they have the potential to be bad microglia and can act as antigen presenting cells to stimulate damaging white blood cell responses. When neural antigens are damaged they can be taken up by macrophages/microglia by a process called phagocytosis. In the cell the neural proteins are digested in the lysosome and then loaded into MHC class I/II to stimulate T cell responses. If they are stimulated in the brain they can cause damage to nerves, as we can show experimentally. They could also help generate damaging antibodies that could contribute to progression.

There are other ways that progressive nerve damage can occur.

CoI Prof Amor and Dr Puentes are part of Team G