Mount Sinai researchers have discovered a new way in which the brain and immune system communicate, which may identify a new therapeutic target for Multiple Sclerosis (MS) and other brain disorders.

Around a million people in the U.S. suffer from multiple sclerosis, a chronic neuroinflammatory disease that typically manifests between ages 20 and 40. This disease causes episodes of neurologic disability that can last for days or weeks, and over time, it can lead to impaired mobility, reduced cognition, paralysis, and premature death. Unfortunately, no cure for MS currently exists.

Researchers from the Cardiovascular Research Institute at Mount Sinai have uncovered a previously unknown way in which the brain and immune system communicate with each other.

In a study published today in the journal Immunity, the team demonstrated how the inflammatory protein interleukin-3 (IL-3) coordinates this cellular communication, which can trigger the recruitment of immune cells from the bloodstream to the brain, exacerbating brain inflammation and worsening MS pathology.

IL-3 has been associated with several autoimmune and inflammatory disorders, but its role in the brain has been vastly understudied.

This discovery may lead to the identification of a new therapeutic target for MS and other brain disorders, as well as deepen our understanding of the communication between the brain and the immune system.

“While we’ve known that brain cells and immune cells are important to multiple sclerosis, the pathways or proteins that act as messengers to mediate communication between these disparate cell populations are poorly understood,” explains senior author Cameron McAlpine. “We’ve identified a previously unknown biological pathway in MS involving IL-3 as a mediator of cross-talk between brain and immune cells and an important regulator of brain inflammation.”

Since it was first identified decades ago, IL-3 has been linked to many diseases. The same Mount Sinai Cardiovascular Research Institute team discovered its relation to Alzheimer’s disease and numerous inflammatory and immunological illnesses. But nothing is known about how it functions in the brain.

The researchers conducted an investigation into the pathophysiology of IL-3 in multiple sclerosis (MS) using human samples and mouse models. They discovered that MS patients had higher levels of IL-3 in their cerebrospinal fluid, which serves as a cushion and protein highway for the brain, compared to healthy individuals.

The team used four unique mouse models to identify the major sources of IL-3 in the central nervous system, which were found to be astrocytes and infiltrating immune cells (T cells). They also observed that other immune cells, such as microglia and infiltrating myeloid cells, responded to IL-3 by expressing its receptor, IL3-Ra. Deleting IL-3 or IL-3Ra led to a significant reduction in immune cell infiltration and inflammation, as well as an improvement in clinical MS symptoms in the mice.

Afterward, the researchers revisited human samples and conducted single nuclear sequencing on brain cells obtained from six healthy individuals and an additional six individuals with MS.

According to the lead author Máté Kiss, PhD, who is a postdoctoral fellow at the Cardiovascular Research Institute at Mount Sinai, their research revealed the presence of IL-3Ra-expressing myeloid cells in the brains of MS patients.

“And evidence that these cells are programmed and wired for inflammation and immune cell recruitment, processes that are detrimental in MS.

“This is a critical finding because in MS patients, myeloid cell IL-3Ra expression and IL-3 levels in the cerebrospinal fluid correlate with worse brain inflammation and MS severity.”

By finding a new way in which MS gets worse, the study team has shown that IL-3 signaling could be a good new treatment target.

“Biologics and small molecules targeting IL-3 signaling have been used in cancer therapy,” adds Dr. McAlpine, and their new “work suggests that this pathway could be therapeutically targeted to not only treat MS, but other neuroinflammatory conditions like Alzheimer’s disease and dementia as well. However, further work is needed to formally test this.”

Image Credit: Getty