Researchers uncover key biological pathway for MS

Study probes how cross-talk between brain, immune cells affects inflammation

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by Steve Bryson, PhD |

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Interleukin-3 (IL-3), an inflammatory signaling protein, seems to coordinate the recruitment of immune cells from the blood into the brain, leading to worsening inflammation and symptoms related to multiple sclerosis (MS), a study revealed.

Targeting IL-3-mediated communication may be an effective therapeutic strategy for MS and other brain disorders, the researchers noted.

“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, PhD, said in a press release. McAlpine is the study’s lead author and professor of medicine and neuroscience at the Icahn School of Medicine at Mount Sinai, in New York.

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Details of the discovery were published in the journal Immunity, in the study  “Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.”

MS is an inflammatory disease that involves an immune-mediated attack on the central nervous system (CNS), which consists of the brain and spinal cord. The infiltration of immune cells into the CNS from the bloodstream is a hallmark of MS and drives much of the disease-causing inflammation.

However, the underlying mechanisms in the brain that stimulate immune cell infiltration in MS are unknown.

“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,” McAlpine said.

IL-3 is a multifunctional immune signaling protein and growth factor implicated in autoimmune diseases, but in inflammatory conditions of the CNS, its role remains undefined.

To shed more light on this, McAlpine and colleagues first examined levels of IL-3 in the cerebrospinal fluid (CSF) — the clear liquid surrounding the CNS — in 36 people diagnosed with relapsing-remitting MS (RRMS) compared with 29 age-matched unaffected individuals. The team found elevated levels of the molecule in MS patients.

EAE mouse model

To investigate potential MS-related mechanisms, the team investigated IL-3 function in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used MS mouse model.

IL-3 was significantly higher in the spinal cord of EAE mice compared with controls. Also, EAE mice engineered to lack IL-3 had improved clinical scores, indicating less-severe disease, and showed reduced loss of the myelin sheath, which is the fatty coating on nerve fibers that is damaged in MS.

“These data suggest that IL-3 contributes to demyelination and worsens neuronal integrity, aggravating EAE severity,” the team wrote.

Moreover, an IL-3 deficiency did not influence immune cell numbers in the blood, but significantly reduced the number of EAE-relevant immune cells in the spinal cord at peak disease severity. A lack of IL-3 also suppressed the production of spinal cord chemoattractants, which are molecules that stimulate the recruitment of immune cells.

“These findings suggest IL-3 plays a [disease-causing] role in the [spinal cord] by driving local inflammation and immune cell recruitment during the [early] phase of EAE, leading to paralysis and disability,” the team wrote.

Further experiments confirmed the major sources of IL-3 in the CNS of EAE were infiltrating immune T-cells and astrocytes, a family of nerve support cells that populate the CNS.

Two types of immune cells were found to respond to IL-3 by producing its receptor, called IL3-Ra. This included microglia, primary immune cells of the CNS, and infiltrating myeloid cells, a family of immune cells originating in the bone marrow.

Deleting IL-3 or IL-3Ra in EAE mice significantly reduced immune cell infiltration into the CNS and its associated inflammation while improving MS symptoms.

Analyzing the biological pathway

To explore whether IL-3 is involved in MS, researchers isolated and analyzed brain cells from tissue collected from six MS patients and six unaffected individuals. Initial work confirmed the inflammatory properties of myeloid cells in MS lesions, or regions of myelin damage.

While IL-3Ra was expressed widely by all CNS cells and in the lesions of MS patients, its expression was elevated significantly in myeloid cells from MS patients compared with unaffected controls. Some myeloid cells were specifically programmed for immune cell recruitment, which is relevant in MS.

“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,” said Máté Kiss, PhD, lead study author and a postdoctoral fellow 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,” Kiss said.

The researchers noted that the therapeutic targeting of IL-3-mediated communication may curb immune cell infiltration, demyelination, and clinical symptoms.

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

The study was funded by the National Institutes of Health and the Cure Alzheimer’s Fund.