Scientists at the Karolinska Institute in Sweden have developed a new disease model for neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) that can be used to develop new immunotherapies. The model is described in a paper (“Fatal Demyelinating Disease Is Induced by Monocyte-Derived Macrophages in the Absence of TGF-β Signaling”) in Nature Immunology.
“The cytokine transforming growth factor-β (TGF-β) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-β is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature. Under defined host conditions, circulating monocytes can compete for the microglial niche and give rise to long-lived monocyte-derived macrophages residing in the central nervous system (CNS). Whether monocytes require TGF-β for colonization of the microglial niche and maintenance of CNS integrity is unknown,” write the investigators.
“We found that abrogation of TGF-βsignaling in CX3CR1+ monocyte-derived macrophages led to rapid onset of a progressive and fatal demyelinating motor disease characterized by myelin-laden giant macrophages throughout the spinal cord. Tgfbr2-deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF-β is thus crucial for the functional integration of monocytes into the CNS microenvironment.”
All of the body’s organs contain macrophages, which consume bacteria and other foreign bodies. However, macrophages are also specialized according to the organ in which they operate; in the brain they are known as microglia, and researchers believe that this specialization is controlled by the cytokine TGF-β.
In a healthy brain, microglia are involved in interneuronal communication and the renewal of myelin, the insulating sheaths enveloping axons of nerve cells that enable the transmission of nerve impulses. In diseases like MS and ALS, monocytes can enter the brain via the blood, be transformed into inflammatory cells, and cause damage to the neurons and the myelin sheath.
The researchers behind the current study had a hypothesis that TGF-β may program monocytes from being inflammatory cells to becoming microglia-like cells.
“We already knew that TGF-β is produced in the brain and is important for giving microglia their specialized functions,” says first author Harald Lund, doctoral student at the department of clinical neuroscience, Karolinska Institute. “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.”
The researchers first used a mouse model in which the animal’s own microglia could be removed. This lead to a rapid influx of monocytes into the brain and spinal cord, which gave rise to new microglia-like cells, and the mice displayed no pathological symptoms. But when the researchers then switched off the TGF-β receptors on the new microglia-like cells, they started to consume large parts of the myelin in the spinal cord. The mice quickly developed a deadly neurodegenerative disease, the symptoms of which were similar to those of ALS.
The disease model can explain a mechanism that is active in neuroinflammatory and neurodegenerative diseases, and could be used to develop and test new immunotherapies, according to the researchers. Today there are no effective treatments.
“There are many deadly neurodegenerative diseases in humans, but [there is also] a lack of experimental models for developing new immunotherapies,” says Bob Harris, D.Phil, at the Centre for Molecular Medicine, Karolinska University Hospital and the department of clinical neuroscience, Karolinska Institute. “This new disease model will be a valuable addition to our research program, and we hope that the next study will result in a new, effective therapy.”