Role of Immune Cells and Early Treatment Seen in Mouse Study
Suppressing the activation of nerve macrophages — a type of immune cell involved in Charcot-Marie-Tooth (CMT) type 1 — from birth lessened nerve damage and partially preserved motor function in a mouse model of CMT type 1A (CMT1A), a study shows.
These findings contrast with those previously reported for the same approach at 3 months of age, indicating that there is an early and narrow therapeutic time window in CMT1A models that may also be true for people.
The data further emphasizes the damaging role nerve macrophages play in this CMT type.
The study, “Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot-Marie-Tooth 1A,” was published in Glia.
CMT is a group of inherited progressive disorders that affect the peripheral nervous system (PNS), which controls movement and sensation in the limbs.
CMT type 1, the most common form of CMT, is characterized by progressive demyelination, or loss of myelin, the protective sheath around nerve fibers (axons), that enables fast neuronal communication.
Myelin is formed by a type of cell called Schwann cells in peripheral nerves.
The most common subtype of CMT type 1, CMT1A is caused by a duplication of the PMP22 gene, which provides the instructions to produce a protein of the same name that’s a key component of the myelin sheath. Excess PMP22 protein not only affects myelin’s structure, but also triggers Schwann cells’ death.
While PNS macrophages are known to help repair nerves after an injury by engulfing and breaking down myelin debris, they can also adopt damaging functions in several neurological conditions, including CMT type 1, evidence suggests.
In a previous study, a team of researchers in Germany showed that low-grade macrophage-related peripheral nerve inflammation contributed to CMT disease processes in mouse models.
Later experiments found that suppressing macrophage activation from three months onwards significantly reduced the number of these cells, lessened axonal damage, and improved muscle strength in CMT type 1X and 1B mouse models.
But this approach — using PLX5622, an oral suppressor of a receptor protein involved in macrophage activation called CSF-1R — failed to have the same benefits in a CMT1A mouse model, despite also reducing nerve macrophage numbers.
“This was unexpected since previous studies identified macrophages [as contributors] to disease severity in the same CMT1A model,” the researchers wrote.
The researchers evaluated whether nerve damage in the CMT1A mouse model could be alleviated if the strategy were applied earlier.
This involved giving PLX5622-containing food to lactating mothers until weaning, and to respective progeny from weaning to 6 months.
This significantly reduced the number of macrophages, myelin-engulfing macrophages, and demyelinated or thinly myelinated axons in peripheral nerves, compared with no treatment.
It was also associated with preventing a decline in nerve function and grip strength in these mice, indicating that early treatment helped to preserve motor function.
Also, suppressing macrophage activation significantly lowered the levels of a marker of Schwann cells’ abnormal maturation — seen in this mouse model and known to promote myelin loss — supporting an early macrophage impact in this abnormal process.
These results suggested that targeting macrophages from birth “is necessary for mitigating [nerve damage] and functional decline in [the CMT1A mouse model], possibly explaining the inefficacy of our previous PLX5622 treatment approach in this model,” the researchers wrote.
Starting treatment at four weeks of age failed to lessen demyelination, “suggesting a rather narrow time window for successful treatment,” they added.
These findings “underscore the targetable role of macrophage-mediated inflammation in peripheral nerves of inherited [nerve-damaging diseases], but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients,” the research team wrote.
While the role of macrophages after this critical therapeutic window has closed is unclear, “it is conceivable that the remaining macrophages, possibly independent of CSF-1R, are still sufficient to mediate demyelination,” the researchers wrote.
Future studies of macrophages and their myelin-engulfing functions in early treated, late treated, and untreated mouse models of CMT1A may help clarify these cells’ role over time.
Despite showing promise, this approach would also lead to suppressing microglia, a macrophage-like cell with a key role in immune response, which needs to be seriously considered, the team noted.
“Another caveat is the need for an early onset of treatment in CMT1A models that certainly makes the translation to clinics problematic,” they wrote.
The researchers noted that physical exercise was shown to be a safe way to reduce nerve damage in a model of CMT type 1X, and that its benefits were likely linked to reduced macrophage activation.
“It would be interesting to investigate whether this and possibly other approaches in treating CMT1A are also dependent on early onset,” and “if so, our present study may be of substantial help to understand therapeutic failures in CMT1A when the respective treatment approaches started in adult individuals,” the team concluded.
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