The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets

Abstract

In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases.

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

“…The emerging results from preclinical in vitro and in vivo studies investigating the role of MIF in ALS suggest that MIF may exert potential protective effects in ALS [27]. The pathogenesis of ALS is still unknown, but as previously indicated, mutant SOD1 could play a key role in this pathology [31] through the mitochondrial accumulation of mutated SOD1 that causes mitochondrial dysfunction and subsequent death of motor neurons [38].…”

“…However, because of its pleiotropic biological functions, during the last decades, many studies have investigated the involvement of MIF in neurodegenerative diseases [27]. The emerging results suggest that MIF may play both a protective or pathogenetic role in neurodegenerative disorders, in particular with a dichotomic role in AD and Parkinson disease (PD), a potential protective action in amyotrophic lateral sclerosis (ALS), and a possible pathogenetic role in Huntington disease (HD).…”

“…ALS is a progressive neurodegenerative disease characterized by the death of alpha motor neurons provoked by heterogeneous pathogenetic pathways that involve the oxidative stress, the neuronal inflammation with immune cells infiltrating the CNS, the mitochondrial dysfunction, RNA splicing errors, and errors in protein conformation [27,28]. According to a study conducted in 2016, the incidence of ALS is approximately 1-2.6 cases per 100,000 people per year and that the prevalence is approximately 6 cases per 100,000 [29].…”

Amyotropyc Lateral Sclerosis and Endogenous -Esogenous Toxicological Movens: New model to verify other Pharmacological Strategies

“…Following in lammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identi ied as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease.We review the evidence on the involvement of CNS macrophages in neuroin lammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of some brain diseases" [7].…”

In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod

“…Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration [1], which represents the most frequent neuroinflammatory disease in young adults, with a mean age of diagnosis of about 30 years and a worldwide prevalence rate of 30.1 cases per 100,000 population in 2016 [2].…”