Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Abstract

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

Neuroimmune Crosstalk Between the Peripheral and the Central Immune System in Amyotrophic Lateral Sclerosis

“…Inflammation is widespread in the CNS in ALS ( Beers and Appel, 2019 ; Liu et al, 2021 ). Glial cells, including microglia and astrocytes, trigger neuroinflammatory reactions, interact with infiltrated peripheral immune cells and eventually induce or accelerate neuronal death in CNS in ALS ( Cragnolini et al, 2020 ).…”

“…However, researchers have recently realized that there is a continuum of phenotypes between M1 and M2 in ALS ( Li et al, 2019 ), such as disease-associated microglia (DAM) ( Krasemann et al, 2017 ; Dols-Icardo et al, 2020 ) and receptor-interacting protein kinase 1 (RIPK1)—regulated inflammatory microglia (RRIMs) ( Mifflin et al, 2021 ). In general, accumulating studies have proven that microglia show an anti-inflammatory phenotype and protect MNs at the onset of the disease, while end-stage microglia shift to a proinflammatory phenotype and aggravate the neurodegeneration of MNs in ALS ( Liu et al, 2021 ; Masrori et al, 2022 ). Astrocytes are the most common glial cells in the brain, maintain the CNS barriers ( Signorile et al, 2021 ), secrete neurotrophic and neuroprotective factors, regulate neurotransmitter uptake and recycling, and promote neurogenesis ( Gharbi et al, 2020 ).…”

Comparing the potential of microglia preparations generated using different human iPSC-based differentiation methods to model microglia-mediated mechanisms of amyotrophic lateral sclerosis pathophysiology

“…It is reasonable to postulate that the success of these investigations will depend on whether or not human iPSC-derived microglia preparations will comprise those specific subtypes that are more relevant to the biological questions under study. A case in point: neuroinflammatory responses mediated by microglia in ALS are heterogeneous, resulting in the presence of distinct subsets of activated microglia that are believed to interact with disease-specific motor neurons in regionally-defined patterns (Dachet et al ., 2019; Maniatis et al ., 2019; Cipollina et al ., 2020; Liu et al ., 2021). More generally, the field of nervous system disease modeling using human iPSCs is increasingly recognizing the importance of including the in vivo heterogeneity of the induced cells among the factors that need to be considered when designing ideal, disease-relevant cellular assays (Hedegaard et al ., 2020; Stifani, 2021; Giacomelli et al ., 2022).…”

“…The study of the mechanisms underlying the roles of microglia in ALS pathophysiology, as well as other neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease, has benefitted from the availability of animal experimental model systems (reviewed by Thonhoff et al ., 2018; Beers & Appel, 2019; Karanfilian et al ., 2020; Liu et al ., 2021). However, numerous species-specific differences in gene expression exist between murine and human microglia.…”

Advances on Cellular Clonotypic Immunity in Amyotrophic Lateral Sclerosis

“…A strong involvement of immune system has been also documented. Precisely, it is well recognized the role of innate immunity, having a pivotal part in the homeostasis of central nervous system (CNS) in inducing neuroinflammation for restraining infections and eliminating pathogens, cell debris, and aggregated or misfold proteins, as well as in ASL, where neuroinflammation is continuous, harmful for CNS cells and constitutes the typical hallmark (3,4). While, adaptive, or better clonotypic, immunity (5) is emerging in recent years in the studies on CNS health and disease, as a fundamental component with a double function, first mediating immune-surveillance and defense against neurotropic viruses (6,7), as well as maintaining CNS homeostasis and integrity, and promoting neurogenesis and improving cognitive function.…”