The transition of microglia from Dr. Jekyll to Mr. Hyde (as discussed in the main post) is influenced by many other cells in the brain. Some cells, including the nerve cells, can actively prevent microglia from becoming the more inflammatory Mr. Hyde. In a healthy brain, the nerve cells are helping themselves by keeping the microglia in a more supportive role. As these nerve cells die off in ALS however, the brakes are released and microglia are able to become more destructive. As discussed in the main post, Regulatory T cells help to keep microglia in a protective state during early stages. But as the disease progresses, other T cells seem to take over and influence microglia to become inflammatory and destructive.
Mr. Hyde microglia release lots of damaging, inflammatory molecules into the brain, which then have effects on other cells besides just the nerve cells. The astrocytes pictured above are not immune cells but play an important role in protecting nerve cells in the healthy brain and helping them to communicate their messages. Astrocytes are located near the Blood-Brain-Barrier which puts them in a prime location to influence cells outside of the brain (those immune cells that are in the bloodstream). The communication between microglia and astrocytes amps up the inflammation and leads to the recruitment of immune cells into the brain where access would normally be forbidden.
Involvement of immune cells in ALS is very complicated with lots of different types of cells talking to one another. While Regulatory T cells try to maintain a “civil” conversation, the interaction of all of these cells ends up being very heated and damaging to the motor neurons. ALS is not exactly an immune-mediated disease, but the inflammation that results can lead to its progression.