Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Apart from beneficial roles in the development of CNS, microglia can be widely involved in various types of neurological disorders, including stroke (Guruswamy & ElAli, ; Kronenberg et al, ), multiple sclerosis (MS) (Bogie, Stinissen, & Hendriks, ; Luo et al, ), AD (Hansen, Hanson, & Sheng, ; Sarlus & Heneka, ), PD (Subramaniam & Federoff, ), sleep disorders (Nadjar, Wigren, & Tremblay, ), amyotrophic lateral sclerosis (ALS) (Geloso et al, ; Liu & Wang, ), Huntington's disease (H. M. Yang, Yang, Huang, Tang, & Guo, ), epilepsy (Eyo, Murugan, & Wu, ; Zhao, Liao, et al, ), gliomas (Hambardzumyan, Gutmann, & Kettenmann, ; Schiffer, Mellai, Bovio, & Annovazzi, ), Prion diseases (Aguzzi & Zhu, ; Obst, Simon, Mancuso, & Gomez‐Nicola, ), psychiatric disorders (Mondelli, Vernon, Turkheimer, Dazzan, & Pariante, ; Prinz & Priller, ; Setiawan et al, ; Singhal & Baune, ), neuropathic pain (Inoue & Tsuda, ; Peng et al, ), adrenomyeloneuropathy (Gong et al, ), and traumatic brain injury (Donat, Scott, Gentleman, & Sastre, ). In general, microglia can be rapidly activated depending upon different stimulatory contexts and environmental changes through diverse molecular and cellular programs, subsequently transforming into the activated state and enhancing the expression of the Toll‐like receptors which sensitively bind microbial structures (Arcuri et al, ).…”

“…Despite that microglia are necessary for repairing the CNS in normal conditions, activated microglia suppress the processes of brain repair by inhibiting the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes via distinct mechanisms including heat shock protein 60 production, NO‐dependent oxidative damage and TNF‐α signaling (Li, Zhang, et al, ; Pang et al, ). Following pathological alterations, extracellular adenosine triphosphate, a source of energy metabolism, produced by dead and injured neurons can in turn activate microglia via purinergic receptors (Liu & Wang, ). Excessive activation of microglia can induce mitochondrial damage and decrease mitochondrial oxygen consumption depending on the degree of their activity, thus influencing total brain energy metabolism and exacerbating disease states (Ghosh, Castillo, Frias, & Swanson, ).…”

Phenotypic heterogeneity of astrocytes in motor neuron disease

“…Such glial vulnerability might be associated with permanent epigenetic changes, prompting an activated glial phenotype. After activation, the neurotoxic astrocyte phenotype seems to be maintained by mitochondria dysfunction, oxidative stress, disrupted inflammatory signaling, endoplasmic reticulum stress and so on . In addition, activation of astrocytes in ALS is associated with increased proliferation and their inability to reach final differentiation, a condition involving decrease in the expression of glutamate transporters, elevated levels of nicotinamide adenine dinucleotide phosphate oxidase, reactive oxygen species and inducible nitric oxide synthase, and increased productions of pro‐inflammatory cytokines/mediators, such as interferon‐γ, prostaglandin D 2 , and transforming growth factor‐β .…”

“…After activation, the neurotoxic astrocyte phenotype seems to be maintained by mitochondria dysfunction, oxidative stress, disrupted inflammatory signaling, endoplasmic reticulum stress and so on. [26][27][28][29] In addition, activation of astrocytes in ALS is associated with increased proliferation and their inability to reach final differentiation, 30,31 a condition involving decrease in the expression of glutamate transporters, 32-34 elevated levels of nicotinamide adenine dinucleotide phosphate oxidase, reactive oxygen species and inducible nitric oxide synthase, 22,26 and increased productions of pro-inflammatory cytokines/mediators, such as interferon-c, 35 prostaglandin D 2 , 21 and transforming growth factor-b. 36 Even wild-type cultured rat neonatal astrocytes can be induced to develop a permanent neurotoxic phenotype when subjected to different acute and sublethal stressful conditions, such as exposure to lipopolysaccharide or peroxynitrite.…”

Characterization of the motor cortex transcriptome supports microgial-related key events in amyotrophic lateral sclerosis

“…The aberrant cytoplasmic aggregation and phosphorylation of the 43-kDa transactive response DNAbinding protein (pTDP-43) represents the main pathological hallmark in the majority of ALS cases at postmortem evaluation and is known to occur in a sequential manner beginning in the motor cortex (1). Although the causes that lead to non-genetic forms of ALS (sporadic ALS) have yet to be fully determined, the presence of neuroinflammation is a consistent feature in the central nervous system of affected subjects (2). Microglia are resident macrophages that belong to the immune system of the central nervous system (CNS), where, as a result of disease conditions, change their gene expression profile to adapt and acquire a reactive state (3).…”