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.

Keywords: ALS (amyotrophic lateral sclerosis); FTD (frontotemporal dementia); iPSC (induced pluripotent stem cells); immune modulatory molecules; immune system; inflammation.

FIGURE 1

Immune cells and their respective locations in the CNS and PNS. Major therapeutic targets are shown and are located either on the cell membrane or in the cytoplasm of cells. The expression of the different targets was indexed through researches with proteinatlas.org. COX-2, cyclooxygenase-2; CSF1R, colony stimulating factor 1 receptor; IL-1R1, interleukin-1 receptor 1; IL-6R, interleukin-6 receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor erythroïd-2-related factor 2; PDE, phosphodiesterase; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PPARγ, peroxisome proliferator-activated receptor gamma; ROCK, Rho-associated protein kinase; S1P, sphingosine-1-phosphate receptor; TKR, tyrosine-kinase receptor; TLR-4, Toll-like receptor 4.

FIGURE 2

Main immune modulatory molecules tested in ALS clinical trials. On the left are listed the different tested molecules with their corresponding colors. On the figure each color dot next to the different cell types shows on which cell the immune modulatory drug is supposed to have an effect. Some cell types targeted by the drugs were well studied in the literature (see Table 4), but in some cases we completed data with theoretical targets (depending on the expression of the target on specific cell types indexed with proteinatlas.org, and for which no information in the literature was found). COX-2, cyclooxygenase-2; CSF1R, colony stimulating factor 1 receptor; IL-1R1, interleukin 1 receptor 1; IL-2, interleukin-2; IL-6R, interleukin 6 receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor erythroïd-2-related factor 2; PDE, phosphodiesterase; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PPARγ, peroxisome proliferator-activated receptor gamma; ROCK, Rho-associated protein kinase; S1P, sphingosine-1-phosphate receptor; TKR, tyrosine-kinase receptor; TLR-4, Toll-like receptor 4.