The brain and immune system were speaking a language we couldn't hear
Inside the brains of people living with multiple sclerosis, a hidden molecular conversation has long been driving destruction without a name. Researchers at Mount Sinai have now identified the messenger — a protein called IL-3 — that coordinates the brain's own cells with invading immune forces, turning a dialogue into a siege. The discovery, emerging from cerebrospinal fluid measurements and mouse models alike, offers science its first precise point of intervention in a disease that quietly dismantles a million American lives. In the long search for a cure, naming the signal is the first act of interrupting it.
- Multiple sclerosis has no cure, and for decades the molecular signals driving its progression have remained hidden — leaving a million Americans with few options beyond managing decline.
- Mount Sinai researchers found that IL-3 protein levels are significantly elevated in the cerebrospinal fluid of MS patients, acting as a call to arms that recruits inflammatory immune cells deep into the brain.
- When IL-3 or its receptor was blocked in four different mouse models, immune cell infiltration dropped sharply, inflammation receded, and symptoms visibly improved — a striking proof of concept.
- Single-cell genetic sequencing of human MS brain tissue confirmed the pattern: immune cells primed for inflammation clustered around IL-3 receptors, and their presence tracked directly with disease severity.
- Drugs that block IL-3 already exist in cancer medicine, raising the possibility that a therapeutic bridge to MS — and potentially Alzheimer's and other neuroinflammatory conditions — may already be within reach.
A team at Mount Sinai has mapped a previously invisible conversation inside the brains of people with multiple sclerosis — one between the brain's own cells and immune fighters crossing over from the bloodstream. Published in May 2023 in the journal Immunity, the discovery centers on a protein called interleukin-3, or IL-3, which acts as a messenger that makes the disease worse by orchestrating this cellular dialogue.
Multiple sclerosis is a chronic nervous system disease affecting roughly a million Americans, typically striking in their twenties or thirties. It arrives in episodes of neurological breakdown and can, over decades, steal mobility, cognition, and life itself. Though researchers have long known that both brain and immune cells drive MS progression, the proteins carrying messages between them have remained largely unknown — until now.
Led by assistant professor Cameron McAlpine at the Icahn School of Medicine, the team first measured IL-3 levels in cerebrospinal fluid, finding significantly higher concentrations in MS patients than in healthy individuals. Tracing IL-3 through four mouse models, they identified astrocytes and infiltrating T cells as its primary sources, and found that when IL-3 binds to receptors on microglia and myeloid cells, it triggers a flood of inflammatory immune cells into the brain. Deleting IL-3 or its receptor sharply reduced that infiltration and visibly improved symptoms.
To confirm the pattern in human disease, the team performed single-cell genetic sequencing on brain tissue from MS patients and healthy individuals. In MS brains, immune cells bearing the IL-3 receptor showed clear genetic signatures of inflammation and recruitment — and their abundance correlated directly with disease severity.
The implications reach beyond MS. Drugs blocking IL-3 signaling already exist in cancer treatment, and McAlpine's team suggests they could be repurposed for MS, Alzheimer's, and other neuroinflammatory conditions. The path from mouse models to working treatments remains long, but for the first time, researchers have a specific molecular target — a concrete place to intervene in a conversation that, until now, no one could hear.
A team at Mount Sinai has mapped a previously invisible conversation happening inside the brains of people with multiple sclerosis—one that takes place between the brain's own cells and immune fighters that have crossed over from the bloodstream. The discovery, published in May 2023 in the journal Immunity, centers on a protein called interleukin-3, or IL-3, which acts as a messenger orchestrating this cellular dialogue in ways that make the disease worse.
Multiple sclerosis is a chronic disease of the nervous system that strikes roughly a million Americans, typically in their twenties or thirties. It arrives in episodes—days or weeks of neurological breakdown—and over decades can steal mobility, cognition, and eventually life itself. There is no cure. For years, researchers have known that both brain cells and immune cells play a role in MS progression, but the actual mechanisms by which they communicate, the proteins that carry messages between them, have remained largely opaque. Cameron McAlpine, an assistant professor at the Icahn School of Medicine at Mount Sinai, and his colleagues set out to change that.
They began with a straightforward measurement. In cerebrospinal fluid—the liquid that bathes and protects the brain—they measured IL-3 levels in 29 healthy people and 36 people with MS. The MS patients had significantly higher concentrations. That observation opened a door. Using four different mouse models of the disease, the team traced where IL-3 was coming from and what it was doing. They found that brain cells called astrocytes and infiltrating T cells were the primary sources. More importantly, they discovered that when IL-3 binds to its receptor on other immune cells—microglia and myeloid cells—it triggers those cells to flood into the brain and amplify inflammation. When the researchers deleted either IL-3 or its receptor in their mouse models, immune cell infiltration dropped sharply, inflammation subsided, and the animals' MS symptoms visibly improved.
To confirm this pattern held in actual human disease, the team performed single-cell genetic sequencing on brain tissue from six healthy individuals and six MS patients. In the MS brains, they found immune cells expressing the IL-3 receptor, and these cells bore the genetic signature of inflammation and recruitment—they were, in essence, primed for war. Critically, the levels of these cells and the amount of IL-3 in the cerebrospinal fluid correlated with how severe each patient's brain inflammation and MS symptoms were.
The finding opens a therapeutic possibility. Drugs that block IL-3 signaling already exist—they have been used in cancer treatment. McAlpine and his team suggest that these same tools might be repurposed to treat not only MS but also other diseases driven by brain inflammation, including Alzheimer's disease and dementia. The work is preliminary; the leap from mouse models and human tissue samples to a working treatment will require years of additional research. But for the first time, researchers have a specific molecular target to aim at, a concrete point of intervention in a conversation that, until now, has been largely invisible.
Notable Quotes
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.— Cameron McAlpine, Assistant Professor of Medicine and Neuroscience, Mount Sinai
In MS patients, myeloid cell IL-3Ra expression and IL-3 levels in the cerebrospinal fluid correlate with worse brain inflammation and MS severity.— Máté Kiss, postdoctoral fellow, Mount Sinai Cardiovascular Research Institute
The Hearth Conversation Another angle on the story
Why does it matter that IL-3 is the messenger? Couldn't there be other proteins doing the same thing?
There could be. But IL-3 appears to be a critical hub—it's what coordinates the whole conversation. If you block it, the immune cells don't get recruited into the brain in the same way. That's why it's a target.
So you're saying the brain is calling for help, and IL-3 is the phone call?
More like IL-3 is the language the brain and immune system use to understand each other. The brain cells are saying "we're inflamed," and IL-3 carries that message to immune cells in the blood. Those cells then rush in, which makes things worse in MS.
If blocking IL-3 helps in mice, why can't they just start treating patients now?
Because mouse brains aren't human brains. The biology is similar, but not identical. You have to prove the drug is safe in people and that it actually works the way the theory predicts. That takes time and careful testing.
The study mentions Alzheimer's disease. Is MS and Alzheimer's the same kind of problem?
Not exactly. But they're both neuroinflammatory—the brain is inflamed in both cases. IL-3 seems to be involved in that inflammation in different ways. If you can control IL-3, you might be able to dial down the inflammation in multiple diseases.
What happens to the thousand people with MS while researchers are doing this additional work?
They keep taking the drugs that exist now. Some of those drugs work reasonably well for some people. But they don't stop the disease, and they don't work for everyone. This research is about finding something better, something that addresses the root mechanism rather than just the symptoms.