Byline: Coram. Guevara, Fernando. Ortiz
Glial cell activation and neuroinflammation in multiple sclerosis (MS): MS is an irreversible and progressive central nervous system (CNS) disease which originates in the autoimmune attack of lymphocytes against CNS myelin. This specialized membrane, synthesized by oligodendrocytes (OL) in the CNS, provides metabolic support to axons and allows for saltatory conduction in neurons. The lack of myelin (i.e., demyelination) leads to axonal degeneration, neuronal death, and the consequent neurological disabilities (Franklin and Ffrench-Constant, 2017). Although the causes of MS are still matter of active investigation, the early events preceding the demyelination onset have been characterized in deep. Evidence indicates that there is an increase in the blood-brain barrier (BBB) permeability, followed by the infiltration of CD4+ T lymphocytes, which, in turn, induces the overactivation of microglia and astrocytes present in the white matter. The latter leads to the dysregulation of the inflammatory response, being characterized by an increased concentration of proinflammatory cytokines promoting myelin loss (recently reviewed in Varas and Ortiz, 2019).
After this demyelinating insult, oligodendrocyte precursor cells (OPCs) migrate to the lesioned area, thus giving rise to remyelinating OLs. However, this spontaneous regenerative process is not normally completed, resulting in a low quality (i.e. less dense) myelin, which consequently leads to a functional failure, hence aggravating the neurological symptoms of MS patients (Franklin and Ffrench-Constant, 2017).
Even though there are not available regenerative therapies for MS, one of the most promising treatments is based on the re-generation of OLs which could, in turn, synthesize new myelin in the lesion (Franklin and Ffrench-Constant, 2017). These new OLs must maturate in a complex cellular environment, characterized by glial cell activation and a neuroinflammatory response. As previously stated, early during the demyelination onset, microglia become activate and release proinflammatory cytokines which triggers an inflammatory response. Astrocytes are also activated, either directly by the tissue injury or indirectly by microglial-derived factors such as interleukin 1[sz] (IL-1[sz]), transforming growth factor [sz]1 (TGF-[sz]1) and interferon-a (INF-a). Additionally, astrocytes release IL-23, IL-1[sz], tumor necrosis factor alpha (TNF-a), and IFN-a, all together contributing to the inflammatory scenario (Varas and Ortiz, 2019; Traiffort et al., 2020).
The role of microglia on MS progression has been extensively studied. Activated microglia contributes to disease pathology by secreting proinflammatory cytokines, chemokines, free radicals, and glutamate (Varas and Ortiz, 2019). Besides, microglia would exert a dual role in the process of remyelination. Evidence shows that microglia and peripherally-derived macrophages polarized in the M1 stage would impair myelin repair in a model of lysolecithin-induced demyelinating lesions (an experimental model of MS) by secreting pro-inflammatory interleukins, such as IL-1 [sz], IL-2 and TNF-a. In the same experimental model, M2-macrophages and microglia promotes remyelination by inducing the differentiation of OPCs into OLs (Miron et al, 2013; Traiffort et al., 2020).
Astrocytes would play a dual role by potentiating the demyelination in early stages of the lesion progression, and also promoting myelin repair in later stages of the remyelination process (Varas and Ortiz, 2019; Traiffort et al., 2020). Studies from...