In diseases such as multiple sclerosis (MS), inflammation-induced damage to myelin sheaths in the brain and spinal cord leads to neurodegeneration. New findings that tie together monocyte development and cytokine signaling now shed important insight that may lead to new immunotherapies. The work, focused on transforming growth factor beta (TGF-β), comes from a team led by Karolinska Institutet researchers and is published recently in Nature Immunology.
“We already knew that TGF-β is produced in the brain and is important for giving microglia their specialised functions. So we figured that monocytes should also respond to TGF-β when they enter the brain. We were curious to see what would happen if the monocytes lost the ability to respond to TGF-β,” said study first author Harald Lund.
The team used a mouse model in which the host’s microglia could be depleted. This led to a colonization of monocytes into the brain and spinal cord. New microglia-like macrophages arose, but no pathological symptoms were observed. Strikingly, when the TGF-β receptors were turned off, the new microglia-like cells began to consume the myelin in the spinal cord. This led to rapid neurodegeneration, in the form of the fatal demyelinating motor disease.
In these macrophages lacking the TGF-β receptor, the team found a high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. The team’s paper concluded that “TGF-β is thus crucial for the functional integration of monocytes into the CNS microenvironment.”
"There are many deadly neurodegenerative diseases in humans, but a lack of experimental models for developing new immunotherapies. This new disease model will be a valuable addition to our research programme and we hope that the next study will result in a new, effective therapy,” says study senior co-author Robert Harris.