Multiple Sclerosis: Inflammatory and Neuroglial Aspects

Abstract

Multiple sclerosis (MS) represents the most common acquired demyelinating disorder of the central nervous system (CNS). Its pathogenesis, in parallel with the well-established role of mechanisms pertaining to autoimmunity, involves several key functions of immune, glial and nerve cells. The disease's natural history is complex, heterogeneous and may evolve over a relapsing-remitting (RRMS) or progressive (PPMS/SPMS) course. Acute inflammation, driven by infiltration of peripheral cells in the CNS, is thought to be the most relevant process during the earliest phases and in RRMS, while disruption in glial and neural cells of pathways pertaining to energy metabolism, survival cascades, synaptic and ionic homeostasis are thought to be mostly relevant in long-standing disease, such as in progressive forms. In this complex scenario, many mechanisms originally thought to be distinctive of neurodegenerative disorders are being increasingly recognized as crucial from the beginning of the disease. The present review aims at highlighting mechanisms in common between MS, autoimmune diseases and biology of neurodegenerative disorders. In fact, there is an unmet need to explore new targets that might be involved as master regulators of autoimmunity, inflammation and survival of nerve cells.

Keywords: autoimmunity; mitochondrial dysfunction; multiple sclerosis; neurodegeneration.

Figure 1

The positive feedback loop of hypoxia and inflammation. The low oxygen presence will lead to the activation of NF-κB, m-TOR, HIF1, ATF4, CHOP signaling, all regulators of inflammation. Increased levels of autoreactive leukocytes and pro-inflammatory cytokines can decrease vasoreactivity, and impair mitochondrial function, which could in turn exacerbate hypoxia.

Figure 2

Overview of relevant pathways to MS pathology regulated by vasoactive peptides.