The immune system is comprised of multiple cell types each capable of specialized functions to protect the body from invading pathogens and promote tissue repair after injury. One cell type, known as monocytes, circulates throughout the organism in the blood and enters tissues to actively phagocytose (eat!) foreign cells and assist in tissue healing. While monocytes can freely enter most bodily tissues, the healthy, normal brain is different as it is sequestered from circulating blood by a tight network of cells known as the blood brain barrier. Thus, the brain must maintain a highly specialized, resident immune cell, known as microglia, to remove harmful invaders and respond to tissue damage.
In certain situations, such as during disease, monocytes can enter the brain and also contribute to tissue repair or disease progression. However, the potential for monocytes to actively replace old or injured microglia is under considerable debate. To address this, Nicholas Varvel, Stefan Grathwohl and colleagues from the German Center for Neurodegenerative Diseases (DZNE) Tübingen and the Hertie Institute for Clinical Brain Research in Tübingen used a transgenic mouse model in which almost all brain microglia cells (>95%) can be removed within two weeks. This was done by introducing a so-called suicide gene into microglia cells and administering a pharmaceutical agent that leads to acute death of the cells. Surprisingly, after the ablation of the microglia, the brain was rapidly repopulated by blood-circulating monocytes. The monocytes appeared similar, but not identical to resident microglia. The newly populated monocytes, evenly dispersed throughout the brain, responded to acute neuronal injury and other stimuli — all activities normally assumed by microglia. Most interestingly, the monocytes were still present in the brain six months – nearly a quarter of the life of a laboratory mouse – after initial colonization.
These studies now published in PNAS provide evidence that blood-circulating monocytes can replace brain resident microglia and take over the essential immune surveillance of the brain. Furthermore, the findings highlight a strong homeostatic mechanism to maintain a resident immune cell within the brain. The observation that the monocytes took up long-term residence in the brain raises the possibility that these cells can be utilized to deliver therapeutic agents into the diseased brain or replace microglia when they become dysfunctional. Can monocytes be exploited to combat the consequences of Alzheimer’s disease and other neurodegenerative diseases? The scientists and their colleagues in the research groups headed by Mathias Jucker are now following exactly this research avenue.
“Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells”, Nicholas H. Varvel, Stefan A. Grathwohl, Frank Baumann, Christian Liebig, Andrea Bosch, Bianca Brawek, Dietmar R. Thald, Israel F. Charo, Frank L. Heppnerf, Adriano Aguzzi, Olga Garaschuk, Richard M. Ransohoff, and Mathias Jucker, Proceedings of the National Academy of Sciences (PNAS): www.pnas.org/cgi/doi/10.1073/pnas.1210150109
Dr. Nicholas Varvel
Deutsches Zentrum für Neurodegenerative Erkrankungen & Hertie-Institut für klinische Hirnforschung, Tübingen (Germany)
Tel.: + 49 7071 29-81924
Dr. Dirk Förger
Head of Press Department
Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn (Germany)
Tel.: + 49 228 43302-260
Director of Communications
Hertie-Institut für klinische Hirnforschung, Tübingen (Germany)
Tel.: + 49 7071 29-88800