A convergence point in MS pathology

The enzyme cytosolic phospholipase A₂ (cPLA₂) may have a key role in the pathogenesis of multiple sclerosis (MS), according to a new study published in Neuron. The findings, made by Kalyvas and David in an animal model of the condition, could lead to better treatments for MS patients.

MS is an inflammatory, demyelinating disease of the central nervous system (CNS). It is thought to involve an autoimmune response in which myelin-reactive cells enter the CNS and initiate the disease. Although the aetiology and pathogenesis of the disorder are still not fully understood, it seems that various causative factors trigger a common mechanism, resulting in the classical pathology of MS — immune cell infiltration into the CNS, a complex inflammatory cascade, and demyelination and axonal damage.

Kalyvas and David looked for a convergence point in the induction of these stereotypical pathologies. They focused on cPLA₂ for two main reasons: first, because many pro-inflammatory chemokines and cytokines produced in the early stages of MS can induce PLA₂; and second, because metabolic products of PLA₂, including arachidonic acid (AA) and lysophosphatidylcholine (LPC), can mediate inflammation and demyelination.

The researchers examined mice with experimental autoimmune encephalomyelitis (EAE), an inflammatory, demyelinating condition induced by immunizing animals against myelin antigens. They found that cPLA₂ was expressed at high levels in endothelial cells and immune cells at EAE lesions. Blocking the enzyme with an AA analogue led to a dramatic reduction in the onset and progression of EAE. The authors showed that cPLA₂ was present at much reduced levels in mice treated with this inhibitor. What's more, they found that inhibiting cPLA₂ in mice with EAE led to a decrease in the expression of many mediators of inflammation, including chemokines and cytokines that are known to induce the expression of cPLA₂ or to be induced by LPC.

These results suggest that cPLA₂ could serve as the common link by which various factors trigger the inflammatory and axonal pathologies characteristic of EAE and MS. Studies of potent and specific inhibitors of cPLA₂ as potential treatments for MS are now warranted.