Multiple sclerosis (MS) is a chronic neuro-inflammatory disease affecting approximately one million people in the United States, with symptoms usually appearing between the ages of 20 and 40. Characterized by episodes of neurological disability lasting days or weeks, the disease often progresses over decades and ultimately leads to impaired mobility, impaired cognition, and ultimately paralysis and early death. There is no cure for MS. While brain cells and immune cells are known to be important in multiple sclerosis, the pathways or proteins that serve as messengers to mediate communication between these disparate cell populations are poorly understood. In a study published today in the journal Immunitya team of scientists from the Mount Sinai Institute has described how the inflammatory cytokine interleukin-3 (IL-3) coordinates cell communication and incites the recruitment of myeloid immune cells from the blood to the brain, worsening MS inflammation and pathology.
Since its discovery decades ago, IL-3 has been associated with multiple conditions, such as several inflammatory and autoimmune disorders. But its role in the brain has been largely underestimated. For their current investigation, the scientists used both human samples and mouse models to explore the pathophysiology of IL-3 in MS. They first measured the levels of IL-3 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. Using four unique mouse models, they then learned that resident brain cells known as astrocytes and infiltrating T cells are the major sources of IL-3 in the brain. Furthermore, they found that other immune cells known as microglia and infiltrating myeloid cells respond to IL-3 by expressing its receptor, IL3-Ra, and that deletion of IL-3 or IL-3Ra significantly reduces infiltration and l inflammation of the immune cells, greatly improving the clinical symptoms of MS of mice.
The researchers then returned to the human samples and performed single nuclear sequencing of the brain cells of 6 healthy individuals and 6 MS patients. So they found the appearance of IL-3Ra-expressing myeloid cells in the brains of MS patients and evidence that these cells are programmed and wired for inflammation and the recruitment of immune cells, processes that are detrimental in MS. According to them, this is a critical point because in MS patients, IL-3Ra expression of myeloid cells and IL-3 levels in cerebrospinal fluid correlate with worse brain inflammation and severity of the condition. The team implicated IL-3 signaling as a potentially promising new therapeutic target. Small molecules and monoclonal antibodies targeting IL-3 signaling have been used in cancer therapy; and the scientists believe this pathway could be targeted to not only treat MS, but other neuroinflammatory conditions as well.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
Geladaris A et al. Acta Neuropathol. 2023 Apr; 145(4):461-477.
Dolcetti E, Bruno A et al. Mult scler. 2023 Apr; 29(4-5):512-520 .
Singh Gautam A et al. Drug Discov Today. 2023; 28(4):103517.