Researchers at Mount Sinai have discovered that cross-talk between brain cells and peripheral immune cells can modulate the progression of multiple sclerosis (MS). The findings reveal a previously unknown way in which the brain and immune system talk to each other and may identify a new therapeutic target for MS and other brain disorders, according to the scientists.

In a study “Interleukin-3 coordinates glial-peripheral immune crosstalk to initiate multiple sclerosis” in Immunity, the team described how the inflammatory protein interleukin-3 (IL-3) coordinates that cellular communication and incites the recruitment of immune cells from the blood to the brain, exacerbating brain inflammation and worsening MS pathology.

“Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44hiCD4+ T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ),” wrote the investigators.

“Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ+ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity.

“Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.”

“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,” said senior author Cameron McAlpine, PhD, assistant professor of medicine (cardiology), and neuroscience, at the Icahn School of Medicine at Mount Sinai. “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.”

IL-3 has been associated with multiple disorders

Since its discovery decades ago, IL-3 has been associated with multiple disorders. Its link to Alzheimer’s disease was identified through research by the same team from the Cardiovascular Research Institute at Mount Sinai; it has also been linked to several inflammatory and autoimmune disorders. But its role in the brain has been vastly understudied.

For their current investigation, Mount Sinai scientists used both human samples and mouse models to explore the pathophysiology of IL-3 in MS. They first measured IL-3 levels in the cerebrospinal fluid of 29 healthy people and 36 MS patients and found that the latter had higher levels of IL-3 in their cerebrospinal fluid, which acts as a watery cushion and a cellular and protein highway for the brain.

diseased spinal cord
Image of diseased spinal cord showing smaller demyelinated lesions where interleukin-3 is targeted. [Icahn School of Medicine at Mount Sinai]

Using four mouse models, they then learned that resident brain cells known as astrocytes and infiltrating immune cells (T cells) are the major sources of IL-3 in the central nervous system. Moreover, they found that other immune cells—microglia and infiltrating myeloid cells—respond to IL-3 by expressing its receptor, IL3-Ra, and that deleting IL-3 or IL-3Ra significantly reduced immune cell infiltration and inflammation, while noticeably improving the clinical MS symptoms of the mice. The researchers then returned to human samples and performed single nuclear sequencing of brain cells from six healthy individuals and six MS patients.

“We found in the brains of MS patients the appearance of IL-3Ra-expressing myeloid cells, and evidence that these cells are programmed and wired for inflammation and immune cell recruitment, processes that are detrimental in MS,” noted lead author Máté Kiss, PhD, a postdoctoral fellow from the Cardiovascular Research Institute at Mount Sinai. “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.”

In identifying a novel mechanism of MS pathogenesis, the research team implicated IL-3 signaling as a potentially promising new therapeutic target.

“Biologics and small molecules targeting IL-3 signaling have been used in cancer therapy,” said McAlpine, “and our 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.”

Participating in the study was the Center for Systems Biology and the department of radiology at Massachusetts General Hospital and Harvard Medical School, and the Center for Genomic Medicine at Mass General.

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