Pathogenesis of Multiple Sclerosis with Special Consideration of Iron Metabolism, Ferroptosis and Other Forms of Programmed Cell Death

The pathogenesis of multiple sclerosis (MS) is a complex topic that involves many individual aspects, several MS risk factors and various alterations in the immune system. In addition to the aspects still being researched in MS today, such as the activation of pro-inflammatory lymphocytes and macrophages, a particular scientific interest refers to the dysregulation of iron and to ferroptosis as an important form of programmed cell death (PCD), which is closely associated with this dysregulation. These two aspects are particularly significant because the new McDonald criteria include the diagnostic determination of so-called "paramagnetic rim lesions" (PRLs) in MS, which are areas of abnormal iron accumulation visible on magnetic resonance imaging (MRI) scans. Along with other diagnostic criteria, these PRLs are an important criterion for the diagnosis of MS. This review begins with an overall description of pathogenic risk factors and the dysregulation of the immune system. However, the priority of the review is the dysregulation of the cerebral iron balance and ferroptosis, as well as other forms of programmed cell death, which have also been demonstrated in MS: apoptosis, pyroptosis, necroptosis and NETosis. One of the main current findings on the forms of PCD in MS is their non-physiological occurrence in the brain's own cells such as oligodendrocytes and neurons, and the extensive protection of pro-inflammatory cells from the occurrence of PCD. Emerging evidence indicates that ferroptosis occurs at an early stage in MS and appears to play a role in its pathogenesis. This review will present the distinct characteristics of the various PCDs in MS, alongside other pathological mechanisms, genetic factors, and current experimental approaches of therapeutic concepts that affect especially ferroptosis and pyroptosis. The aim is to provide an overview on iron dysregulation and forms of PCD as key aspects for understanding the pathogenesis of MS.