Neuroinflammation plays a central and complex role in multiple sclerosis (MS), a chronic autoimmune disease that affects the central nervous system (CNS). At its core, MS involves the immune system mistakenly attacking the protective myelin sheath that surrounds nerve fibers, leading to demyelination, nerve damage, and progressive neurological disability. Neuroinflammation is the process by which immune cells and inflammatory molecules become activated within the CNS, driving much of the tissue damage and clinical symptoms seen in MS.
In MS, neuroinflammation is primarily mediated by immune cells such as microglia, macrophages, and infiltrating lymphocytes that enter the brain and spinal cord. Microglia are the resident immune cells of the CNS and serve as the first line of defense. When activated abnormally, they release pro-inflammatory cytokines and reactive oxygen species that contribute to myelin and neuronal injury. Border-associated macrophages and other myeloid cells also participate by promoting inflammation and recruiting additional immune cells into the CNS. This inflammatory environment disrupts normal neural function and leads to the characteristic lesions seen in MS.
One key aspect of neuroinflammation in MS is the dysregulation of immune signaling pathways. For example, certain receptors on myeloid cells, such as SLAMF5, have been found to regulate the activation and inflammatory behavior of these cells. Blocking or genetically disrupting SLAMF5 reduces the inflammatory response of brain myeloid cells, decreases infiltration of harmful T cells, and lessens disease severity in experimental models. This highlights how specific molecular interactions within CNS immune cells can drive or mitigate neuroinflammation.
Neuroinflammation in MS is not just about immune attack; it also involves a failure of protective and repair mechanisms. Glial cells, including astrocytes and microglia, normally support neurons by releasing neurotrophic factors—proteins that promote cell survival, reduce inflammation, and encourage remyelination by helping oligodendrocyte precursor cells mature and repair damaged myelin. In MS, this protective glial function is impaired, allowing inflammation and neurodegeneration to smolder and progress. This ongoing, low-level inflammation within the CNS, often called smoldering neuroinflammation, can be largely invisible but steadily contributes to disability accumulation over time.
Another important factor linked to neuroinflammation in MS is iron dysregulation. Iron is essential for many brain functions, but when its balance is disturbed, it can catalyze oxidative damage and worsen inflammation. Excess iron accumulation in certain brain regions has been associated with increased neurodegeneration and disease progression in MS. This suggests that iron metabolism is intertwined with neuroinflammatory processes and could be a target for future therapies.
The inflammatory environment in MS also creates a state of “virtual hypoxia,” where oxygen supply and demand in the CNS are imbalanced, further stressing neurons and glial cells. This hypoxic-like condition promotes angiogenesis (formation of new blood vessels) and alters metabolic pathways, which can exacerbate inflammation and tissue damage.
At the molecular level, metabolites from pathways such as the kynurenine pathway modulate inflammation and neuronal health. Imbalances in these metabolites can mimic or worsen neuroinflammatory damage, influencing disease activity and progression.
In summary, neuroinflammation in MS is a multifaceted process involving the activation and dysregulation of CNS immune cells, impaired protective glial functions, metabolic disturbances like iron imbalance, and altered molecular signaling pathways. This inflammation drives demyelination, neuronal injury, and the progressive neurological decline characteristic of MS. Understanding these mechanisms opens avenues for targeted therapies that not only suppress harmful immune responses but also promote repair and neuroprotection within the CNS.
